rs41274636

chr10-54527809-T-Cchr10-54527809-T-G

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.157+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0838 in 1,603,330 control chromosomes in the GnomAD database, including 5,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (702 hom., cov: 32)
  • Exomes 𝑓: 0.083 (5223 hom.)
• Consequence: PCDH15 NM_033056.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.001148
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.746

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 10-54527809-T-C is Benign according to our data. Variant chr10-54527809-T-C is described in ClinVar as [Benign]. Clinvar id is 46444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54527809-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_001384140.1	c.157+3A>G		splice_donor_region_variant, intron_variant		ENST00000644397.2
PCDH15	NM_033056.4	c.157+3A>G		splice_donor_region_variant, intron_variant		ENST00000320301.11
LOC105378311	NR_134503.1	n.88-40756T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.157+3A>G		splice_donor_region_variant, intron_variant		1	NM_033056.4
PCDH15	ENST00000644397.2	c.157+3A>G		splice_donor_region_variant, intron_variant			NM_001384140.1
	ENST00000422842.1	n.88-40756T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0937 AC: 14225 AN: 151842 Hom.: 696 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0689

Gnomad ASJ AF: 0.0514

Gnomad EAS AF: 0.0832

Gnomad SAS AF: 0.0570

Gnomad FIN AF: 0.0606

Gnomad MID AF: 0.0924

Gnomad NFE AF: 0.0839

Gnomad OTH AF: 0.0872

GnomAD3 exomes AF: 0.0782 AC: 19457 AN: 248754 Hom.: 878 AF XY: 0.0761 AC XY: 10222 AN XY: 134368

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.0646

Gnomad ASJ exome AF: 0.0501

Gnomad EAS exome AF: 0.0740

Gnomad SAS exome AF: 0.0542

Gnomad FIN exome AF: 0.0654

Gnomad NFE exome AF: 0.0860

Gnomad OTH exome AF: 0.0842

GnomAD4 exome AF: 0.0827 AC: 120086 AN: 1451368 Hom.: 5223 Cov.: 30 AF XY: 0.0818 AC XY: 59065 AN XY: 722368

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.0662

Gnomad4 ASJ exome AF: 0.0505

Gnomad4 EAS exome AF: 0.0830

Gnomad4 SAS exome AF: 0.0551

Gnomad4 FIN exome AF: 0.0639

Gnomad4 NFE exome AF: 0.0853

Gnomad4 OTH exome AF: 0.0853

GnomAD4 genome AF: 0.0938 AC: 14252 AN: 151962 Hom.: 702 Cov.: 32 AF XY: 0.0914 AC XY: 6794 AN XY: 74300

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.0687

Gnomad4 ASJ AF: 0.0514

Gnomad4 EAS AF: 0.0834

Gnomad4 SAS AF: 0.0577

Gnomad4 FIN AF: 0.0606

Gnomad4 NFE AF: 0.0839

Gnomad4 OTH AF: 0.0858

Alfa AF: 0.0875 Hom.: 388

Bravo AF: 0.0979

Asia WGS AF: 0.0800 AC: 278 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2009	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 08, 2013	- -

Usher syndrome type 1F Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Usher syndrome type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	18
Dann	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.034
SpliceAI score (max)		0.010		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: rs41274636; hg19: chr10-56287569; COSMIC: COSV57391208;