5-140848828-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_031857.2(PCDHA9):c.333C>A(p.Asp111Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (6407 hom., cov: 25)
  • Exomes 𝑓: 0.31 (107562 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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017764568).
• BP6: Variant 5-140848828-C-A is Benign according to our data. Variant chr5-140848828-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3058838.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 10956 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHA9	NM_031857.2	c.333C>A	p.Asp111Glu	missense_variant	1/4	ENST00000532602.2
PCDHA1	NM_018900.4	c.2394+60144C>A		intron_variant		ENST00000504120.4
PCDHA2	NM_018905.3	c.2388+51476C>A		intron_variant		ENST00000526136.2
PCDHA3	NM_018906.3	c.2394+45237C>A		intron_variant		ENST00000522353.3
PCDHA4	NM_018907.4	c.2385+39256C>A		intron_variant		ENST00000530339.2
PCDHA5	NM_018908.3	c.2352+24701C>A		intron_variant		ENST00000529859.2
PCDHA6	NM_018909.4	c.2394+18343C>A		intron_variant		ENST00000529310.6
PCDHA7	NM_018910.3	c.2355+12090C>A		intron_variant		ENST00000525929.2
PCDHA8	NM_018911.3	c.2394+5113C>A		intron_variant		ENST00000531613.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHA9	ENST00000532602.2	c.333C>A	p.Asp111Glu	missense_variant	1/4	1	NM_031857.2	P1
PCDHA1	ENST00000504120.4	c.2394+60144C>A		intron_variant		1	NM_018900.4	P1
PCDHA3	ENST00000522353.3	c.2394+45237C>A		intron_variant		1	NM_018906.3	P1
PCDHA7	ENST00000525929.2	c.2355+12090C>A		intron_variant		1	NM_018910.3	P1
PCDHA2	ENST00000526136.2	c.2388+51476C>A		intron_variant		1	NM_018905.3	P1
PCDHA6	ENST00000529310.6	c.2394+18343C>A		intron_variant		1	NM_018909.4	P1
PCDHA5	ENST00000529859.2	c.2352+24701C>A		intron_variant		1	NM_018908.3	P1
PCDHA4	ENST00000530339.2	c.2385+39256C>A		intron_variant		1	NM_018907.4	P1
PCDHA8	ENST00000531613.2	c.2394+5113C>A		intron_variant		1	NM_018911.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 33403 AN: 141860 Hom.: 6398 Cov.: 25 FAILED QC

Gnomad AFR AF: 0.0761

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.256

GnomAD3 exomes AF: 0.161 AC: 33477 AN: 208254 Hom.: 10956 AF XY: 0.159 AC XY: 17804 AN XY: 112102

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.0614

Gnomad SAS exome AF: 0.195

Gnomad FIN exome AF: 0.195

Gnomad NFE exome AF: 0.173

Gnomad OTH exome AF: 0.193

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.311 AC: 422125 AN: 1356112 Hom.: 107562 Cov.: 58 AF XY: 0.312 AC XY: 210089 AN XY: 674022

Gnomad4 AFR exome AF: 0.0719

Gnomad4 AMR exome AF: 0.311

Gnomad4 ASJ exome AF: 0.284

Gnomad4 EAS exome AF: 0.126

Gnomad4 SAS exome AF: 0.327

Gnomad4 FIN exome AF: 0.331

Gnomad4 NFE exome AF: 0.325

Gnomad4 OTH exome AF: 0.296

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.235 AC: 33414 AN: 141972 Hom.: 6407 Cov.: 25 AF XY: 0.235 AC XY: 16254 AN XY: 69196

Gnomad4 AFR AF: 0.0759

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.270

Gnomad4 EAS AF: 0.132

Gnomad4 SAS AF: 0.314

Gnomad4 FIN AF: 0.297

Gnomad4 NFE AF: 0.316

Gnomad4 OTH AF: 0.256

Alfa AF: 0.264 Hom.: 663

ESP6500AA AF: 0.00828 AC: 36

ESP6500EA AF: 0.108 AC: 891

ExAC AF: 0.164 AC: 19637

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	0.11
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	15
Dann	Benign	0.96
DEOGEN2	Benign	0.025	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.60	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.58	N;N
MutationTaster	Benign	4.7e-10	P;P;P;P;P;P;P;P;P;P;P;P;P;P
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.043
Sift	Benign	0.20	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.011
MutPred		0.53		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
ClinPred		0.0079	T
GERP RS		1.1
Varity_R		0.17
gMVP		0.29

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: rs17844323; hg19: chr5-140228413; COSMIC: COSV65323080; COSMIC: COSV65323080;