chr5-140786647-G-A

Position:

• chr5-140786647-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_018900.4(PCDHA1):​c.357G>A​(p.Val119Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000572 in 1,614,260 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (2 hom.)
• Consequence: PCDHA1 NM_018900.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.227

Genes affected

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]

ENSG00000279726 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 5-140786647-G-A is Benign according to our data. Variant chr5-140786647-G-A is described in ClinVar as [Benign]. Clinvar id is 730554.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.227 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDHA1	NM_018900.4	c.357G>A	p.Val119Val	synonymous_variant	1/4	ENST00000504120.4	NP_061723.1
PCDHA1	NM_031410.2	c.357G>A	p.Val119Val	synonymous_variant	1/1		NP_113598.1
PCDHA1	NM_031411.3	c.357G>A	p.Val119Val	synonymous_variant	1/4		NP_113599.1
PCDHA@		n.140786647G>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHA1	ENST00000504120.4	c.357G>A	p.Val119Val	synonymous_variant	1/4	1	NM_018900.4	ENSP00000420840.3
PCDHA1	ENST00000394633.7	c.357G>A	p.Val119Val	synonymous_variant	1/4	1		ENSP00000378129.3
PCDHA1	ENST00000378133.4	c.357G>A	p.Val119Val	synonymous_variant	1/1	6		ENSP00000367373.3
ENSG00000279726	ENST00000655235.1	n.2865C>T		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 420 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000756 AC: 190 AN: 251480 Hom.: 2 AF XY: 0.000544 AC XY: 74 AN XY: 135916

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000345 AC: 504 AN: 1461888 Hom.: 2 Cov.: 32 AF XY: 0.000272 AC XY: 198 AN XY: 727246

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.000811

GnomAD4 genome AF: 0.00276 AC: 420 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.00271 AC XY: 202 AN XY: 74522

Gnomad4 AFR AF: 0.00972

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00232 Hom.: 1

Bravo AF: 0.00330

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.61

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: rs73278757; hg19: chr5-140166232; COSMIC: COSV100974278; COSMIC: COSV100974278;