5-140848597-C-G

Position:

• chr5-140848597-C-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_031857.2(PCDHA9):​c.102C>G​(p.Ser34=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,580,604 control chromosomes in the GnomAD database, including 857 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0069 (52 hom., cov: 28)
  • Exomes 𝑓: 0.0037 (805 hom.)
• Consequence: PCDHA9 NM_031857.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -4.20

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 5-140848597-C-G is Benign according to our data. Variant chr5-140848597-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2655769.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-4.2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00693 (1041/150206) while in subpopulation SAS AF= 0.0205 (97/4734). AF 95% confidence interval is 0.0172. There are 52 homozygotes in gnomad4. There are 453 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 52 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHA9	NM_031857.2	c.102C>G	p.Ser34=	synonymous_variant	1/4	ENST00000532602.2
PCDHA1	NM_018900.4	c.2394+59913C>G		intron_variant		ENST00000504120.4
PCDHA2	NM_018905.3	c.2388+51245C>G		intron_variant		ENST00000526136.2
PCDHA3	NM_018906.3	c.2394+45006C>G		intron_variant		ENST00000522353.3
PCDHA4	NM_018907.4	c.2385+39025C>G		intron_variant		ENST00000530339.2
PCDHA5	NM_018908.3	c.2352+24470C>G		intron_variant		ENST00000529859.2
PCDHA6	NM_018909.4	c.2394+18112C>G		intron_variant		ENST00000529310.6
PCDHA7	NM_018910.3	c.2355+11859C>G		intron_variant		ENST00000525929.2
PCDHA8	NM_018911.3	c.2394+4882C>G		intron_variant		ENST00000531613.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHA9	ENST00000532602.2	c.102C>G	p.Ser34=	synonymous_variant	1/4	1	NM_031857.2	P1
PCDHA1	ENST00000504120.4	c.2394+59913C>G		intron_variant		1	NM_018900.4	P1
PCDHA3	ENST00000522353.3	c.2394+45006C>G		intron_variant		1	NM_018906.3	P1
PCDHA7	ENST00000525929.2	c.2355+11859C>G		intron_variant		1	NM_018910.3	P1
PCDHA2	ENST00000526136.2	c.2388+51245C>G		intron_variant		1	NM_018905.3	P1
PCDHA6	ENST00000529310.6	c.2394+18112C>G		intron_variant		1	NM_018909.4	P1
PCDHA5	ENST00000529859.2	c.2352+24470C>G		intron_variant		1	NM_018908.3	P1
PCDHA4	ENST00000530339.2	c.2385+39025C>G		intron_variant		1	NM_018907.4	P1
PCDHA8	ENST00000531613.2	c.2394+4882C>G		intron_variant		1	NM_018911.3	P1

Frequencies

GnomAD3 genomes AF: 0.00695 AC: 1043 AN: 150090 Hom.: 52 Cov.: 28

Gnomad AFR AF: 0.00132

Gnomad AMI AF: 0.00221

Gnomad AMR AF: 0.00892

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.00105

Gnomad MID AF: 0.0226

Gnomad NFE AF: 0.00921

Gnomad OTH AF: 0.0112

GnomAD3 exomes AF: 0.00297 AC: 734 AN: 246734 Hom.: 68 AF XY: 0.00313 AC XY: 417 AN XY: 133378

Gnomad AFR exome AF: 0.000313

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00602

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00511

Gnomad FIN exome AF: 0.000650

Gnomad NFE exome AF: 0.00393

Gnomad OTH exome AF: 0.00233

GnomAD4 exome AF: 0.00373 AC: 5333 AN: 1430398 Hom.: 805 Cov.: 80 AF XY: 0.00415 AC XY: 2950 AN XY: 711502

Gnomad4 AFR exome AF: 0.000931

Gnomad4 AMR exome AF: 0.00373

Gnomad4 ASJ exome AF: 0.0177

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.00155

Gnomad4 NFE exome AF: 0.00299

Gnomad4 OTH exome AF: 0.00556

GnomAD4 genome AF: 0.00693 AC: 1041 AN: 150206 Hom.: 52 Cov.: 28 AF XY: 0.00617 AC XY: 453 AN XY: 73396

Gnomad4 AFR AF: 0.00131

Gnomad4 AMR AF: 0.00891

Gnomad4 ASJ AF: 0.0282

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0205

Gnomad4 FIN AF: 0.00105

Gnomad4 NFE AF: 0.00921

Gnomad4 OTH AF: 0.0110

Asia WGS AF: 0.00261 AC: 9 AN: 3466

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

PCDHA9-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

PCDHA1: BS2; PCDHA2: BS2; PCDHA3: BS2; PCDHA4: BS2; PCDHA5: BS2; PCDHA6: BS2; PCDHA7: BS2; PCDHA8: BS2; PCDHA9: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.2
DANN	Benign	0.71

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: rs151001396; hg19: chr5-140228182; COSMIC: COSV65325709; COSMIC: COSV65325709;