chr10-54195725-A-G

Position:

chr10-54195725-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001384140.1(PCDH15):c.1263T>C(p.Thr421Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,613,080 control chromosomes in the GnomAD database, including 23,428 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 6057 hom., cov: 32)

Exomes 𝑓: 0.14 ( 17371 hom. )

Consequence

PCDH15
NM_001384140.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: -0.223

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 10-54195725-A-G is Benign according to our data. Variant chr10-54195725-A-G is described in ClinVar as [Benign]. Clinvar id is 46439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54195725-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.223 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.483 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.1263T>C	p.Thr421Thr	synonymous_variant	11/33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 linkuse as main transcript	c.1263T>C	p.Thr421Thr	synonymous_variant	11/38	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.1263T>C	p.Thr421Thr	synonymous_variant	11/33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.1263T>C	p.Thr421Thr	synonymous_variant	11/38		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.230

AC:

35002

AN:

151942

Hom.:

6041

Cov.:

show subpopulations

Gnomad AFR

AF:

0.489

Gnomad AMI

AF:

0.0857

Gnomad AMR

AF:

0.199

Gnomad ASJ

AF:

0.118

Gnomad EAS

AF:

0.0910

Gnomad SAS

AF:

0.181

Gnomad FIN

AF:

0.108

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.208

GnomAD3 exomes

AF:

0.165

AC:

41539

AN:

251378

Hom.:

4654

AF XY:

0.158

AC XY:

21510

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.496

Gnomad AMR exome

AF:

0.211

Gnomad ASJ exome

AF:

0.120

Gnomad EAS exome

AF:

0.0950

Gnomad SAS exome

AF:

0.183

Gnomad FIN exome

AF:

0.114

Gnomad NFE exome

AF:

0.125

Gnomad OTH exome

AF:

0.157

GnomAD4 exome

AF:

0.140

AC:

203946

AN:

1461022

Hom.:

17371

Cov.:

AF XY:

0.139

AC XY:

100829

AN XY:

726858

show subpopulations

Gnomad4 AFR exome

AF:

0.504

Gnomad4 AMR exome

AF:

0.212

Gnomad4 ASJ exome

AF:

0.119

Gnomad4 EAS exome

AF:

0.0669

Gnomad4 SAS exome

AF:

0.179

Gnomad4 FIN exome

AF:

0.113

Gnomad4 NFE exome

AF:

0.126

Gnomad4 OTH exome

AF:

0.156

GnomAD4 genome

AF:

0.231

AC:

35063

AN:

152058

Hom.:

6057

Cov.:

AF XY:

0.226

AC XY:

16830

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.488

Gnomad4 AMR

AF:

0.199

Gnomad4 ASJ

AF:

0.118

Gnomad4 EAS

AF:

0.0910

Gnomad4 SAS

AF:

0.181

Gnomad4 FIN

AF:

0.108

Gnomad4 NFE

AF:

0.122

Gnomad4 OTH

AF:

0.211

Alfa

AF:

0.150

Hom.:

3527

Bravo

AF:

0.253

Asia WGS

AF:

0.163

AC:

569

AN:

3478

EpiCase

AF:

0.129

EpiControl

AF:

0.124

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

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	-	- -

Usher syndrome type 1F

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 11, 2022

- -

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

BayesDel_noAF

Benign

-0.81

CADD

Benign

7.9

DANN

Benign

0.36

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