rs11594958

Variant names:

• chr10-54369306-A-G
• rs11594958
• NM_033056.4:c.319-31T>C

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: 0.649
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 23

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 262150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.319-31T>C		intron_variant	Intron 4 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.319-31T>C		intron_variant	Intron 4 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.319-31T>C		intron_variant	Intron 4 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.319-31T>C		intron_variant	Intron 4 of 37		NM_001384140.1	ENSP00000495195.1

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

GnomAD2 exomes AF: 0.198 AC: 47796 AN: 241600 AF XY: 0.198

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 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

African (AFR) AF: 0.228 AC: 7566 AN: 33210

American (AMR) AF: 0.241 AC: 10623 AN: 44150

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 4829 AN: 25928

East Asian (EAS) AF: 0.0661 AC: 2602 AN: 39388

South Asian (SAS) AF: 0.214 AC: 18333 AN: 85632

European-Finnish (FIN) AF: 0.158 AC: 8242 AN: 52140

Middle Eastern (MID) AF: 0.241 AC: 1369 AN: 5672

European-Non Finnish (NFE) AF: 0.195 AC: 215055 AN: 1104726

Other (OTH) AF: 0.198 AC: 11876 AN: 59870

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

African (AFR) AF: 0.225 AC: 9322 AN: 41508

American (AMR) AF: 0.233 AC: 3543 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 665 AN: 3472

East Asian (EAS) AF: 0.0927 AC: 480 AN: 5178

South Asian (SAS) AF: 0.208 AC: 1005 AN: 4830

European-Finnish (FIN) AF: 0.145 AC: 1537 AN: 10578

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.196 AC: 13291 AN: 67944

Other (OTH) AF: 0.211 AC: 446 AN: 2114

Alfa AF: 0.203 Hom.: 1077

Bravo AF: 0.210

Asia WGS AF: 0.149 AC: 517 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1F Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.2
DANN	Benign	0.48
PhyloP100		0.65
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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