rs7921598

Positions:

• chr10-54195725-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.223

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]

ACMG classification

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	c.1263T>C	p.Thr421Thr	synonymous_variant	11/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	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	c.1263T>C	p.Thr421Thr	synonymous_variant	11/33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.1263T>C	p.Thr421Thr	synonymous_variant	11/38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.230 AC: 35002 AN: 151942 Hom.: 6041 Cov.: 32

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

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.: 33 AF XY: 0.139 AC XY: 100829 AN XY: 726858

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.: 32 AF XY: 0.226 AC XY: 16830 AN XY: 74326

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:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other: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

Other links and lift over

dbSNP: rs7921598; hg19: chr10-55955485; COSMIC: COSV57302866;