rs2593107

chr10-53959892-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033056.4(PCDH15):c.3010-48G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,412,740 control chromosomes in the GnomAD database, including 354,828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38165 hom., cov: 31)
  • Exomes 𝑓: 0.71 (316663 hom.)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.277

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 (BayesDel_noAF=-0.83).
• BP6: Variant 10-53959892-C-T is Benign according to our data. Variant chr10-53959892-C-T is described in ClinVar as [Benign]. Clinvar id is 262149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53959892-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_001384140.1	c.3010-48G>A		intron_variant		ENST00000644397.2
PCDH15	NM_033056.4	c.3010-48G>A		intron_variant		ENST00000320301.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.3010-48G>A		intron_variant		1	NM_033056.4
PCDH15	ENST00000644397.2	c.3010-48G>A		intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.705 AC: 107166 AN: 151918 Hom.: 38144 Cov.: 31

Gnomad AFR AF: 0.646

Gnomad AMI AF: 0.831

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.787

Gnomad EAS AF: 0.868

Gnomad SAS AF: 0.737

Gnomad FIN AF: 0.729

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.692

Gnomad OTH AF: 0.735

GnomAD3 exomes AF: 0.744 AC: 180148 AN: 242168 Hom.: 67549 AF XY: 0.739 AC XY: 96784 AN XY: 130912

Gnomad AFR exome AF: 0.655

Gnomad AMR exome AF: 0.872

Gnomad ASJ exome AF: 0.787

Gnomad EAS exome AF: 0.884

Gnomad SAS exome AF: 0.732

Gnomad FIN exome AF: 0.729

Gnomad NFE exome AF: 0.696

Gnomad OTH exome AF: 0.737

GnomAD4 exome AF: 0.708 AC: 892354 AN: 1260706 Hom.: 316663 Cov.: 17 AF XY: 0.708 AC XY: 451331 AN XY: 637060

Gnomad4 AFR exome AF: 0.657

Gnomad4 AMR exome AF: 0.862

Gnomad4 ASJ exome AF: 0.791

Gnomad4 EAS exome AF: 0.878

Gnomad4 SAS exome AF: 0.734

Gnomad4 FIN exome AF: 0.720

Gnomad4 NFE exome AF: 0.689

Gnomad4 OTH exome AF: 0.721

GnomAD4 genome AF: 0.705 AC: 107240 AN: 152034 Hom.: 38165 Cov.: 31 AF XY: 0.713 AC XY: 53005 AN XY: 74322

Gnomad4 AFR AF: 0.646

Gnomad4 AMR AF: 0.812

Gnomad4 ASJ AF: 0.787

Gnomad4 EAS AF: 0.869

Gnomad4 SAS AF: 0.737

Gnomad4 FIN AF: 0.729

Gnomad4 NFE AF: 0.692

Gnomad4 OTH AF: 0.733

Alfa AF: 0.715 Hom.: 7725

Bravo AF: 0.712

Asia WGS AF: 0.780 AC: 2716 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal recessive nonsyndromic hearing loss 23 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Usher syndrome type 1F Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.53
Dann	Benign	0.39

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: rs2593107; hg19: chr10-55719652;