rs149208928

chr10-53809503-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000395445.6(PCDH15):c.4541A>C(p.Glu1514Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000904 in 1,611,732 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (8 hom.)
• Consequence: PCDH15 ENST00000395445.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.06

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046368837).
• BP6: Variant 10-53809503-T-G is Benign according to our data. Variant chr10-53809503-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 178678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809503-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00527 (802/152300) while in subpopulation AFR AF= 0.0183 (760/41556). AF 95% confidence interval is 0.0172. There are 8 homozygotes in gnomad4. There are 372 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_001384140.1	c.4671+1053A>C		intron_variant		ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000644397.2	c.4671+1053A>C		intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.00528 AC: 803 AN: 152182 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00128 AC: 314 AN: 246268 Hom.: 3 AF XY: 0.00104 AC XY: 139 AN XY: 133722

Gnomad AFR exome AF: 0.0181

Gnomad AMR exome AF: 0.000792

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: 0.0000537

Gnomad OTH exome AF: 0.000503

GnomAD4 exome AF: 0.000449 AC: 655 AN: 1459432 Hom.: 8 Cov.: 33 AF XY: 0.000394 AC XY: 286 AN XY: 725830

Gnomad4 AFR exome AF: 0.0166

Gnomad4 AMR exome AF: 0.000813

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000990

Gnomad4 OTH exome AF: 0.000830

GnomAD4 genome AF: 0.00527 AC: 802 AN: 152300 Hom.: 8 Cov.: 32 AF XY: 0.00500 AC XY: 372 AN XY: 74468

Gnomad4 AFR AF: 0.0183

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.0226 Hom.: 2358

Bravo AF: 0.00585

ESP6500AA AF: 0.0191 AC: 60

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00152 AC: 183

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 19, 2013	Glu1521Ala in Exon 37A of PCDH15: This variant is not expected to have clinical significance because it has been identified in 1.9% (60/3136) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs149208928). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 03, 2023	- -

PCDH15-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	0.096
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.72	T;T;T;T;T;T
MetaRNN	Benign	0.0046	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	D;D;N;N;N;N;N;N
PROVEAN	Benign	-1.2	N;N;N;.;.;.
REVEL	Benign	0.063
Sift	Uncertain	0.0080	D;D;D;.;.;.
Sift4G	Benign	0.11	T;T;T;T;T;T
Vest4		0.60
MVP		0.56
ClinPred		0.011	T
GERP RS		5.9

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: rs149208928; hg19: chr10-55569263;