chr10-54132882-T-C

Position:

chr10-54132882-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000320301.11(PCDH15):c.1910A>G(p.Asn637Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0271 in 1,612,316 control chromosomes in the GnomAD database, including 791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 86 hom., cov: 32)

Exomes 𝑓: 0.027 ( 705 hom. )

Consequence

PCDH15
ENST00000320301.11 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 6.18

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009124845).

BP6

Variant 10-54132882-T-C is Benign according to our data. Variant chr10-54132882-T-C is described in ClinVar as [Benign]. Clinvar id is 46448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54132882-T-C is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4 linkuse as main transcript	c.1910A>G	p.Asn637Ser	missense_variant	15/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1 linkuse as main transcript	c.1910A>G	p.Asn637Ser	missense_variant	15/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 linkuse as main transcript	c.1910A>G	p.Asn637Ser	missense_variant	15/33	1	NM_033056.4	ENSP00000322604		Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.1910A>G	p.Asn637Ser	missense_variant	15/38		NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes

AF:

0.0295

AC:

4487

AN:

151962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0356

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0279

Gnomad ASJ

AF:

0.0326

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.0487

Gnomad FIN

AF:

0.0270

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0270

Gnomad OTH

AF:

0.0397

GnomAD3 exomes

AF:

0.0275

AC:

6832

AN:

248534

Hom.:

131

AF XY:

0.0290

AC XY:

3899

AN XY:

134282

show subpopulations

Gnomad AFR exome

AF:

0.0370

Gnomad AMR exome

AF:

0.0174

Gnomad ASJ exome

AF:

0.0332

Gnomad EAS exome

AF:

0.00205

Gnomad SAS exome

AF:

0.0485

Gnomad FIN exome

AF:

0.0238

Gnomad NFE exome

AF:

0.0274

Gnomad OTH exome

AF:

0.0344

GnomAD4 exome

AF:

0.0269

AC:

39249

AN:

1460236

Hom.:

705

Cov.:

AF XY:

0.0277

AC XY:

20129

AN XY:

726292

show subpopulations

Gnomad4 AFR exome

AF:

0.0367

Gnomad4 AMR exome

AF:

0.0179

Gnomad4 ASJ exome

AF:

0.0347

Gnomad4 EAS exome

AF:

0.00104

Gnomad4 SAS exome

AF:

0.0496

Gnomad4 FIN exome

AF:

0.0238

Gnomad4 NFE exome

AF:

0.0256

Gnomad4 OTH exome

AF:

0.0305

GnomAD4 genome

AF:

0.0295

AC:

4491

AN:

152080

Hom.:

Cov.:

AF XY:

0.0303

AC XY:

2256

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0356

Gnomad4 AMR

AF:

0.0279

Gnomad4 ASJ

AF:

0.0326

Gnomad4 EAS

AF:

0.00155

Gnomad4 SAS

AF:

0.0489

Gnomad4 FIN

AF:

0.0270

Gnomad4 NFE

AF:

0.0270

Gnomad4 OTH

AF:

0.0393

Alfa

AF:

0.0287

Hom.:

125

Bravo

AF:

0.0291

TwinsUK

AF:

0.0216

AC:

ALSPAC

AF:

0.0228

AC:

ESP6500AA

AF:

0.0365

AC:

161

ESP6500EA

AF:

0.0281

AC:

242

ExAC

AF:

0.0280

AC:

3396

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2009	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 21, 2019	- -

Usher syndrome type 1F

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 10, 2020	- -

Autosomal recessive nonsyndromic hearing loss 23

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Usher syndrome type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.018

T;.;.;.;.;T;T;.;T;T;.;.;T;.;T;.;.;.;.;T;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0091

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.17

.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;N

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.6

.;.;.;.;.;.;.;N;N;.;N;N;.;N;.;N;N;N;.;N;N

REVEL

Benign

0.17

Sift

Benign

0.50

.;.;.;.;.;.;.;T;T;.;T;T;.;T;.;T;T;T;.;T;T

Sift4G

Uncertain

0.028

D;.;D;D;D;D;T;T;T;D;D;T;D;D;D;D;D;D;D;D;D

Polyphen

0.95, 0.94, 0.97, 1.0, 0.74, 0.86

.;.;.;.;.;.;.;.;.;.;.;P;.;P;.;D;D;D;.;P;P

Vest4

0.69

MPC

0.070

ClinPred

0.089

GERP RS

3.2

Varity_R

0.15

gMVP

0.31

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

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