rs148772706

Positions:

• chr10-53806942-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 NM_001384140.1(PCDH15):​c.4860G>A​(p.Thr1620=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00408 in 1,613,760 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (14 hom.)
• Consequence: PCDH15 NM_001384140.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.79

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=-0.91).
• BP6: Variant 10-53806942-C-T is Benign according to our data. Variant chr10-53806942-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53806942-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00422 (6174/1461648) while in subpopulation NFE AF= 0.00514 (5711/1111822). AF 95% confidence interval is 0.00503. There are 14 homozygotes in gnomad4_exome. There are 3044 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_001384140.1	c.4860G>A	p.Thr1620=	synonymous_variant	38/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000644397.2	c.4860G>A	p.Thr1620=	synonymous_variant	38/38		NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 412 AN: 151994 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00335

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00460

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00264 AC: 655 AN: 248464 Hom.: 1 AF XY: 0.00264 AC XY: 357 AN XY: 134980

Gnomad AFR exome AF: 0.000972

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.00445

Gnomad OTH exome AF: 0.00397

GnomAD4 exome AF: 0.00422 AC: 6174 AN: 1461648 Hom.: 14 Cov.: 33 AF XY: 0.00419 AC XY: 3044 AN XY: 727108

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00250

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.00514

Gnomad4 OTH exome AF: 0.00292

GnomAD4 genome AF: 0.00271 AC: 412 AN: 152112 Hom.: 1 Cov.: 32 AF XY: 0.00264 AC XY: 196 AN XY: 74346

Gnomad4 AFR AF: 0.000795

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00460

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00311 Hom.: 0

Bravo AF: 0.00255

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00584

EpiControl AF: 0.00338

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Thr1562Thr in Exon 36C 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 0.4% (20/5444) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs148772706). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PCDH15: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.019
DANN	Benign	0.32

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148772706; hg19: chr10-55566702;