rs251354

Positions:

• chr5-140849501-C-G
• chr5-140849501-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_031857.2(PCDHA9):​c.1006C>G​(p.Leu336Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 146,412 control chromosomes in the GnomAD database, including 32,935 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.65 (32935 hom., cov: 26)
  • Exomes 𝑓: 0.63 (311102 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCDHA9 NM_031857.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.33

Genes affected

PCDHA9 (HGNC:8675): (protocadherin alpha 9) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA1 (HGNC:8663): (protocadherin alpha 1) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA3 (HGNC:8669): (protocadherin alpha 3) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA6 (HGNC:8672): (protocadherin alpha 6) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA8 (HGNC:8674): (protocadherin alpha 8) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA2 (HGNC:8668): (protocadherin alpha 2) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA4 (HGNC:8670): (protocadherin alpha 4) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA7 (HGNC:8673): (protocadherin alpha 7) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA5 (HGNC:8671): (protocadherin alpha 5) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

ENSG00000278907 (HGNC:):

PCDHA@ (HGNC:8662):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.6165788E-5).
• BP6: Variant 5-140849501-C-G is Benign according to our data. Variant chr5-140849501-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3059467.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDHA9	NM_031857.2	c.1006C>G	p.Leu336Val	missense_variant	1/4	ENST00000532602.2	NP_114063.1
PCDHA1	NM_018900.4	c.2394+60817C>G		intron_variant		ENST00000504120.4	NP_061723.1
PCDHA3	NM_018906.3	c.2394+45910C>G		intron_variant		ENST00000522353.3	NP_061729.1
PCDHA6	NM_018909.4	c.2394+19016C>G		intron_variant		ENST00000529310.6	NP_061732.1
PCDHA8	NM_018911.3	c.2394+5786C>G		intron_variant		ENST00000531613.2	NP_061734.1
PCDHA2	NM_018905.3	c.2388+52149C>G		intron_variant		ENST00000526136.2	NP_061728.1
PCDHA4	NM_018907.4	c.2385+39929C>G		intron_variant		ENST00000530339.2	NP_061730.1
PCDHA7	NM_018910.3	c.2355+12763C>G		intron_variant		ENST00000525929.2	NP_061733.1
PCDHA5	NM_018908.3	c.2352+25374C>G		intron_variant		ENST00000529859.2	NP_061731.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHA9	ENST00000532602.2	c.1006C>G	p.Leu336Val	missense_variant	1/4	1	NM_031857.2	ENSP00000436042.2
PCDHA1	ENST00000504120.4	c.2394+60817C>G		intron_variant		1	NM_018900.4	ENSP00000420840.3
PCDHA3	ENST00000522353.3	c.2394+45910C>G		intron_variant		1	NM_018906.3	ENSP00000429808.2
PCDHA6	ENST00000529310.6	c.2394+19016C>G		intron_variant		1	NM_018909.4	ENSP00000433378.1
PCDHA8	ENST00000531613.2	c.2394+5786C>G		intron_variant		1	NM_018911.3	ENSP00000434655.1
PCDHA2	ENST00000526136.2	c.2388+52149C>G		intron_variant		1	NM_018905.3	ENSP00000431748.1
PCDHA4	ENST00000530339.2	c.2385+39929C>G		intron_variant		1	NM_018907.4	ENSP00000435300.1
PCDHA7	ENST00000525929.2	c.2355+12763C>G		intron_variant		1	NM_018910.3	ENSP00000436426.1
PCDHA5	ENST00000529859.2	c.2352+25374C>G		intron_variant		1	NM_018908.3	ENSP00000436557.1

Frequencies

GnomAD3 genomes AF: 0.645 AC: 94370 AN: 146296 Hom.: 32885 Cov.: 26

Gnomad AFR AF: 0.712

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.617

Gnomad ASJ AF: 0.637

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.683

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.638

GnomAD3 exomes AF: 0.622 AC: 154753 AN: 248990 Hom.: 52851 AF XY: 0.625 AC XY: 84092 AN XY: 134562

Gnomad AFR exome AF: 0.718

Gnomad AMR exome AF: 0.565

Gnomad ASJ exome AF: 0.654

Gnomad EAS exome AF: 0.477

Gnomad SAS exome AF: 0.650

Gnomad FIN exome AF: 0.686

Gnomad NFE exome AF: 0.625

Gnomad OTH exome AF: 0.629

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.625 AC: 891068 AN: 1424946 Hom.: 311102 Cov.: 64 AF XY: 0.626 AC XY: 444273 AN XY: 710176

Gnomad4 AFR exome AF: 0.726

Gnomad4 AMR exome AF: 0.572

Gnomad4 ASJ exome AF: 0.652

Gnomad4 EAS exome AF: 0.493

Gnomad4 SAS exome AF: 0.644

Gnomad4 FIN exome AF: 0.681

Gnomad4 NFE exome AF: 0.624

Gnomad4 OTH exome AF: 0.627

GnomAD4 genome AF: 0.645 AC: 94477 AN: 146412 Hom.: 32935 Cov.: 26 AF XY: 0.646 AC XY: 46037 AN XY: 71274

Gnomad4 AFR AF: 0.712

Gnomad4 AMR AF: 0.617

Gnomad4 ASJ AF: 0.637

Gnomad4 EAS AF: 0.484

Gnomad4 SAS AF: 0.654

Gnomad4 FIN AF: 0.683

Gnomad4 NFE AF: 0.623

Gnomad4 OTH AF: 0.639

Alfa AF: 0.641 Hom.: 2656

ESP6500AA AF: 0.702 AC: 3082

ESP6500EA AF: 0.614 AC: 5252

ExAC AF: 0.625 AC: 75425

Asia WGS AF: 0.638 AC: 2213 AN: 3468

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PCDHA9-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.5
DANN	Benign	0.78
DEOGEN2	Benign	0.018	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0027	N
LIST_S2	Benign	0.49	T;T
MetaRNN	Benign	0.000036	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.2	N;N
PROVEAN	Benign	2.3	N;N
REVEL	Benign	0.033
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.040
ClinPred		0.0013	T
GERP RS		2.0
Varity_R		0.046
gMVP		0.040

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs251354; hg19: chr5-140229086; COSMIC: COSV65324934;