rs3812658

Variant names:

• chr10-54020155-G-A
• rs3812658
• NM_033056.4:c.2751+37C>T

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.2751+37C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 1,578,954 control chromosomes in the GnomAD database, including 390,397 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (29492 hom., cov: 31)
  • Exomes 𝑓: 0.70 (360905 hom.)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.118
• Publications: 9 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=-0.87).
• BP6: Variant 10-54020155-G-A is Benign according to our data. Variant chr10-54020155-G-A is described in ClinVar as Benign. ClinVar VariationId is 262147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.736 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.2751+37C>T		intron_variant	Intron 20 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.2751+37C>T		intron_variant	Intron 20 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.2751+37C>T		intron_variant	Intron 20 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.2751+37C>T		intron_variant	Intron 20 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.593 AC: 89924 AN: 151724 Hom.: 29489 Cov.: 31

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.667

Gnomad AMR AF: 0.702

Gnomad ASJ AF: 0.736

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.690

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.742

Gnomad OTH AF: 0.642

GnomAD2 exomes AF: 0.647 AC: 160334 AN: 247826 AF XY: 0.646

Gnomad AFR exome AF: 0.309

Gnomad AMR exome AF: 0.745

Gnomad ASJ exome AF: 0.740

Gnomad EAS exome AF: 0.336

Gnomad FIN exome AF: 0.689

Gnomad NFE exome AF: 0.744

Gnomad OTH exome AF: 0.711

GnomAD4 exome AF: 0.701 AC: 1000658 AN: 1427112 Hom.: 360905 Cov.: 25 AF XY: 0.696 AC XY: 495701 AN XY: 712210

African (AFR) AF: 0.305 AC: 9944 AN: 32612

American (AMR) AF: 0.741 AC: 32963 AN: 44496

Ashkenazi Jewish (ASJ) AF: 0.744 AC: 19291 AN: 25918

East Asian (EAS) AF: 0.275 AC: 10841 AN: 39442

South Asian (SAS) AF: 0.483 AC: 41253 AN: 85444

European-Finnish (FIN) AF: 0.692 AC: 36505 AN: 52718

Middle Eastern (MID) AF: 0.755 AC: 4305 AN: 5704

European-Non Finnish (NFE) AF: 0.745 AC: 805579 AN: 1081534

Other (OTH) AF: 0.675 AC: 39977 AN: 59244

GnomAD4 genome AF: 0.592 AC: 89935 AN: 151842 Hom.: 29492 Cov.: 31 AF XY: 0.589 AC XY: 43672 AN XY: 74208

African (AFR) AF: 0.318 AC: 13167 AN: 41428

American (AMR) AF: 0.702 AC: 10689 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 2552 AN: 3468

East Asian (EAS) AF: 0.292 AC: 1505 AN: 5152

South Asian (SAS) AF: 0.463 AC: 2232 AN: 4822

European-Finnish (FIN) AF: 0.690 AC: 7278 AN: 10550

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.742 AC: 50351 AN: 67894

Other (OTH) AF: 0.636 AC: 1340 AN: 2108

Alfa AF: 0.702 Hom.: 49492

Bravo AF: 0.587

Asia WGS AF: 0.361 AC: 1255 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

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

- -

Autosomal recessive nonsyndromic hearing loss 23 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1F Benign:1

Sep 05, 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	-0.87
CADD	Benign	0.30
DANN	Benign	0.19
PhyloP100		-0.12
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: rs3812658; hg19: chr10-55779915; COSMIC: COSV57320711;