10-53808767-C-T

Position:

• chr10-53808767-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000395445.6(PCDH15):​c.5277G>A​(p.Ala1759=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00787 in 1,612,442 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (52 hom.)
• Consequence: PCDH15 ENST00000395445.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.507

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 10-53808767-C-T is Benign according to our data. Variant chr10-53808767-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 44037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53808767-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.507 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00702 (1068/152200) while in subpopulation NFE AF= 0.00824 (560/68000). AF 95% confidence interval is 0.00767. There are 6 homozygotes in gnomad4. There are 568 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_001384140.1	c.4672-1637G>A		intron_variant		ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000644397.2	c.4672-1637G>A		intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.00702 AC: 1067 AN: 152082 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00662

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00823

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00699 AC: 1718 AN: 245870 Hom.: 13 AF XY: 0.00693 AC XY: 926 AN XY: 133562

Gnomad AFR exome AF: 0.00741

Gnomad AMR exome AF: 0.000704

Gnomad ASJ exome AF: 0.00222

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000666

Gnomad FIN exome AF: 0.0190

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.00567

GnomAD4 exome AF: 0.00796 AC: 11629 AN: 1460242 Hom.: 52 Cov.: 31 AF XY: 0.00776 AC XY: 5636 AN XY: 726220

Gnomad4 AFR exome AF: 0.00816

Gnomad4 AMR exome AF: 0.000742

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.0195

Gnomad4 NFE exome AF: 0.00884

Gnomad4 OTH exome AF: 0.00638

GnomAD4 genome AF: 0.00702 AC: 1068 AN: 152200 Hom.: 6 Cov.: 32 AF XY: 0.00764 AC XY: 568 AN XY: 74390

Gnomad4 AFR AF: 0.00662

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0182

Gnomad4 NFE AF: 0.00824

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00705 Hom.: 1

Bravo AF: 0.00566

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PCDH15: BP4, BP7, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Ala1766Ala in Exon 37A of PCDH15: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 0.7% (40/5446) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs139441645). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 11, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.9
DANN	Benign	0.78

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: rs139441645; hg19: chr10-55568527;