rs11594958

chr10-54369306-A-G

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.319-31T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,602,738 control chromosomes in the GnomAD database, including 30,982 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3151 hom., cov: 32)
  • Exomes 𝑓: 0.19 (27831 hom.)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.649

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=-0.8).
• BP6: Variant 10-54369306-A-G is Benign according to our data. Variant chr10-54369306-A-G is described in ClinVar as [Benign]. Clinvar id is 262150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54369306-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_001384140.1	c.319-31T>C		intron_variant		ENST00000644397.2
PCDH15	NM_033056.4	c.319-31T>C		intron_variant		ENST00000320301.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.319-31T>C		intron_variant		1	NM_033056.4
PCDH15	ENST00000644397.2	c.319-31T>C		intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30621 AN: 151904 Hom.: 3145 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.0927

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.213

GnomAD3 exomes AF: 0.198 AC: 47796 AN: 241600 Hom.: 4804 AF XY: 0.198 AC XY: 25901 AN XY: 130636

Gnomad AFR exome AF: 0.227

Gnomad AMR exome AF: 0.239

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.0944

Gnomad SAS exome AF: 0.215

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.193 AC: 280495 AN: 1450716 Hom.: 27831 Cov.: 29 AF XY: 0.194 AC XY: 139910 AN XY: 721660

Gnomad4 AFR exome AF: 0.228

Gnomad4 AMR exome AF: 0.241

Gnomad4 ASJ exome AF: 0.186

Gnomad4 EAS exome AF: 0.0661

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.195

Gnomad4 OTH exome AF: 0.198

GnomAD4 genome AF: 0.202 AC: 30640 AN: 152022 Hom.: 3151 Cov.: 32 AF XY: 0.199 AC XY: 14776 AN XY: 74312

Gnomad4 AFR AF: 0.225

Gnomad4 AMR AF: 0.233

Gnomad4 ASJ AF: 0.192

Gnomad4 EAS AF: 0.0927

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.196

Gnomad4 OTH AF: 0.211

Alfa AF: 0.200 Hom.: 595

Bravo AF: 0.210

Asia WGS AF: 0.149 AC: 517 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

-

- -

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	-0.80
Cadd	Benign	6.2
Dann	Benign	0.48

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: rs11594958; hg19: chr10-56129066; COSMIC: COSV57324883;