rs3812658

Positions:

• chr10-54020155-G-A

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+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

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=-0.87).
• BP6: Variant 10-54020155-G-A is Benign according to our data. Variant chr10-54020155-G-A is described in ClinVar as [Benign]. Clinvar id is 262147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54020155-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
PCDH15	NM_001384140.1	c.2751+37C>T		intron_variant		ENST00000644397.2	NP_001371069.1
PCDH15	NM_033056.4	c.2751+37C>T		intron_variant		ENST00000320301.11	NP_149045.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.2751+37C>T		intron_variant		1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.2751+37C>T		intron_variant			NM_001384140.1	ENSP00000495195

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

GnomAD3 exomes AF: 0.647 AC: 160334 AN: 247826 Hom.: 54923 AF XY: 0.646 AC XY: 86521 AN XY: 134034

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 SAS exome AF: 0.475

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

Gnomad4 AFR exome AF: 0.305

Gnomad4 AMR exome AF: 0.741

Gnomad4 ASJ exome AF: 0.744

Gnomad4 EAS exome AF: 0.275

Gnomad4 SAS exome AF: 0.483

Gnomad4 FIN exome AF: 0.692

Gnomad4 NFE exome AF: 0.745

Gnomad4 OTH exome AF: 0.675

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

Gnomad4 AFR AF: 0.318

Gnomad4 AMR AF: 0.702

Gnomad4 ASJ AF: 0.736

Gnomad4 EAS AF: 0.292

Gnomad4 SAS AF: 0.463

Gnomad4 FIN AF: 0.690

Gnomad4 NFE AF: 0.742

Gnomad4 OTH AF: 0.636

Alfa AF: 0.718 Hom.: 39033

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

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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal recessive nonsyndromic hearing loss 23 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Usher syndrome type 1F Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.30
DANN	Benign	0.19

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: rs3812658; hg19: chr10-55779915; COSMIC: COSV57320711;