Variant rs74609306 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001384140.1(PCDH15):c.5124G>A(p.Lys1708Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.028 in 1,613,826 control chromosomes in the GnomAD database, including 740 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 36 hom., cov: 32)

Exomes 𝑓: 0.029 ( 704 hom. )

Consequence

PCDH15
NM_001384140.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0680

Variant links:

Genes affected

PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]

PCDH15 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 10-53806678-C-T is Benign according to our data. Variant chr10-53806678-C-T is described in ClinVar as [Benign]. Clinvar id is 227004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53806678-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.068 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0196 (2978/152230) while in subpopulation NFE AF= 0.033 (2245/68004). AF 95% confidence interval is 0.0319. There are 36 homozygotes in gnomad4. There are 1370 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 36 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_001384140.1 linkuse as main transcript	c.5124G>A	p.Lys1708Lys	synonymous_variant	38/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000644397.2 linkuse as main transcript	c.5124G>A	p.Lys1708Lys	synonymous_variant	38/38		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.0196

AC:

2976

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00541

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0123

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00517

Gnomad FIN

AF:

0.0230

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0330

Gnomad OTH

AF:

0.0183

GnomAD3 exomes

AF:

0.0192

AC:

4769

AN:

248706

Hom.:

AF XY:

0.0190

AC XY:

2562

AN XY:

135132

show subpopulations

Gnomad AFR exome

AF:

0.00421

Gnomad AMR exome

AF:

0.00872

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00539

Gnomad FIN exome

AF:

0.0288

Gnomad NFE exome

AF:

0.0307

Gnomad OTH exome

AF:

0.0236

GnomAD4 exome

AF:

0.0289

AC:

42201

AN:

1461596

Hom.:

704

Cov.:

AF XY:

0.0281

AC XY:

20463

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.00394

Gnomad4 AMR exome

AF:

0.00919

Gnomad4 ASJ exome

AF:

0.00188

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00633

Gnomad4 FIN exome

AF:

0.0286

Gnomad4 NFE exome

AF:

0.0342

Gnomad4 OTH exome

AF:

0.0248

GnomAD4 genome

AF:

0.0196

AC:

2978

AN:

152230

Hom.:

Cov.:

AF XY:

0.0184

AC XY:

1370

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00539

Gnomad4 AMR

AF:

0.0123

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00539

Gnomad4 FIN

AF:

0.0230

Gnomad4 NFE

AF:

0.0330

Gnomad4 OTH

AF:

0.0181

Alfa

AF:

0.0253

Hom.:

Bravo

AF:

0.0173

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0293

EpiControl

AF:

0.0270

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Lys1650Lys in Exon 37 of PCDH15: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 2.8% (154/5446) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs74609306). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

7.2

DANN

Benign

0.49

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over