rs2660169

Variant names:

• chr10-54020149-G-C
• rs2660169
• NM_033056.4:c.2751+43C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-54020149-G-C
• chr10-54020149-G-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+43C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0676 in 1,546,326 control chromosomes in the GnomAD database, including 11,783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (4755 hom., cov: 32)
  • Exomes 𝑓: 0.057 (7028 hom.)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0520
• Publications: 4 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=-0.85).
• BP6: Variant 10-54020149-G-C is Benign according to our data. Variant chr10-54020149-G-C is described in ClinVar as Benign. ClinVar VariationId is 262148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.2751+43C>G		intron_variant	Intron 20 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.2751+43C>G		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+43C>G		intron_variant	Intron 20 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.2751+43C>G		intron_variant	Intron 20 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25218 AN: 151844 Hom.: 4731 Cov.: 32

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0862

Gnomad ASJ AF: 0.0545

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.0276

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0308

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.0941 AC: 23292 AN: 247406 AF XY: 0.0900

Gnomad AFR exome AF: 0.464

Gnomad AMR exome AF: 0.0476

Gnomad ASJ exome AF: 0.0536

Gnomad EAS exome AF: 0.254

Gnomad FIN exome AF: 0.0281

Gnomad NFE exome AF: 0.0295

Gnomad OTH exome AF: 0.0688

GnomAD4 exome AF: 0.0568 AC: 79222 AN: 1394364 Hom.: 7028 Cov.: 23 AF XY: 0.0583 AC XY: 40711 AN XY: 697856

African (AFR) AF: 0.473 AC: 15155 AN: 32056

American (AMR) AF: 0.0506 AC: 2247 AN: 44414

Ashkenazi Jewish (ASJ) AF: 0.0540 AC: 1387 AN: 25696

East Asian (EAS) AF: 0.255 AC: 10023 AN: 39234

South Asian (SAS) AF: 0.150 AC: 12757 AN: 84894

European-Finnish (FIN) AF: 0.0290 AC: 1526 AN: 52550

Middle Eastern (MID) AF: 0.0794 AC: 447 AN: 5630

European-Non Finnish (NFE) AF: 0.0292 AC: 30751 AN: 1051726

Other (OTH) AF: 0.0847 AC: 4929 AN: 58164

GnomAD4 genome AF: 0.166 AC: 25291 AN: 151962 Hom.: 4755 Cov.: 32 AF XY: 0.165 AC XY: 12263 AN XY: 74290

African (AFR) AF: 0.457 AC: 18938 AN: 41416

American (AMR) AF: 0.0861 AC: 1312 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.0545 AC: 189 AN: 3468

East Asian (EAS) AF: 0.262 AC: 1354 AN: 5166

South Asian (SAS) AF: 0.154 AC: 743 AN: 4820

European-Finnish (FIN) AF: 0.0276 AC: 292 AN: 10596

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0308 AC: 2093 AN: 67930

Other (OTH) AF: 0.138 AC: 293 AN: 2116

Alfa AF: 0.0409 Hom.: 113

Bravo AF: 0.183

Asia WGS AF: 0.240 AC: 831 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 16, 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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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	-0.85
CADD	Benign	1.7
DANN	Benign	0.46
PhyloP100		0.052
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: rs2660169; hg19: chr10-55779909; COSMIC: COSV57389215;