rs2660169

chr10-54020149-G-Cchr10-54020149-G-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.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:2
• Conservation: PhyloP100: 0.0520

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=-0.85).
• BP6: Variant 10-54020149-G-C is Benign according to our data. Variant chr10-54020149-G-C is described in ClinVar as [Benign]. Clinvar id is 262148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54020149-G-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
PCDH15	NM_001384140.1	c.2751+43C>G		intron_variant		ENST00000644397.2
PCDH15	NM_033056.4	c.2751+43C>G		intron_variant		ENST00000320301.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.2751+43C>G		intron_variant		1	NM_033056.4
PCDH15	ENST00000644397.2	c.2751+43C>G		intron_variant			NM_001384140.1

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

GnomAD3 exomes AF: 0.0941 AC: 23292 AN: 247406 Hom.: 2945 AF XY: 0.0900 AC XY: 12048 AN XY: 133830

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 SAS exome AF: 0.154

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

Gnomad4 AFR exome AF: 0.473

Gnomad4 AMR exome AF: 0.0506

Gnomad4 ASJ exome AF: 0.0540

Gnomad4 EAS exome AF: 0.255

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.0290

Gnomad4 NFE exome AF: 0.0292

Gnomad4 OTH exome AF: 0.0847

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

Gnomad4 AFR AF: 0.457

Gnomad4 AMR AF: 0.0861

Gnomad4 ASJ AF: 0.0545

Gnomad4 EAS AF: 0.262

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.0276

Gnomad4 NFE AF: 0.0308

Gnomad4 OTH AF: 0.138

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:2

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

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 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	-0.85
Cadd	Benign	1.7
Dann	Benign	0.46

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: rs2660169; hg19: chr10-55779909; COSMIC: COSV57389215;