rs251354

Positions:

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

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin 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 criteria provided, single submitter 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]

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]

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]

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]

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]

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]

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]

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 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 criteria_provided_single_submitter, 1 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	UniProt
PCDHA9	NM_031857.2	c.1006C>G	p.Leu336Val	missense_variant	1/4	ENST00000532602.2
PCDHA1	NM_018900.4	c.2394+60817C>G		intron_variant		ENST00000504120.4
PCDHA2	NM_018905.3	c.2388+52149C>G		intron_variant		ENST00000526136.2
PCDHA3	NM_018906.3	c.2394+45910C>G		intron_variant		ENST00000522353.3
PCDHA4	NM_018907.4	c.2385+39929C>G		intron_variant		ENST00000530339.2
PCDHA5	NM_018908.3	c.2352+25374C>G		intron_variant		ENST00000529859.2
PCDHA6	NM_018909.4	c.2394+19016C>G		intron_variant		ENST00000529310.6
PCDHA7	NM_018910.3	c.2355+12763C>G		intron_variant		ENST00000525929.2
PCDHA8	NM_018911.3	c.2394+5786C>G		intron_variant		ENST00000531613.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHA9	ENST00000532602.2	c.1006C>G	p.Leu336Val	missense_variant	1/4	1	NM_031857.2	P1
PCDHA1	ENST00000504120.4	c.2394+60817C>G		intron_variant		1	NM_018900.4	P1
PCDHA3	ENST00000522353.3	c.2394+45910C>G		intron_variant		1	NM_018906.3	P1
PCDHA7	ENST00000525929.2	c.2355+12763C>G		intron_variant		1	NM_018910.3	P1
PCDHA2	ENST00000526136.2	c.2388+52149C>G		intron_variant		1	NM_018905.3	P1
PCDHA6	ENST00000529310.6	c.2394+19016C>G		intron_variant		1	NM_018909.4	P1
PCDHA5	ENST00000529859.2	c.2352+25374C>G		intron_variant		1	NM_018908.3	P1
PCDHA4	ENST00000530339.2	c.2385+39929C>G		intron_variant		1	NM_018907.4	P1
PCDHA8	ENST00000531613.2	c.2394+5786C>G		intron_variant		1	NM_018911.3	P1
	ENST00000623320.1	n.196G>C		non_coding_transcript_exon_variant	1/1

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: criteria provided, single submitter

Submissions by phenotype

PCDHA9-related disorder Benign:1

Likely benign, criteria provided, single submitter

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
MutationTaster	Benign	0.0098	P;P;P;P;P;P;P;P;P;P;P;P;P;P
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;