10-53810587-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001384140.1(PCDH15):c.4640G>A(p.Gly1547Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00944 in 1,613,770 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (82 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.53

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 (MetaRNN=0.00866279).
• BP6: Variant 10-53810587-C-T is Benign according to our data. Variant chr10-53810587-C-T is described in ClinVar as [Benign]. Clinvar id is 227001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53810587-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00717 (1092/152268) while in subpopulation NFE AF= 0.0107 (727/68016). AF 95% confidence interval is 0.01. There are 11 homozygotes in gnomad4. There are 543 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_001384140.1	c.4640G>A	p.Gly1547Asp	missense_variant	37/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000644397.2	c.4640G>A	p.Gly1547Asp	missense_variant	37/38		NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.00718 AC: 1092 AN: 152150 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0167

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00767 AC: 1908 AN: 248774 Hom.: 9 AF XY: 0.00761 AC XY: 1029 AN XY: 135182

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.00588

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.0159

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.00694

GnomAD4 exome AF: 0.00967 AC: 14138 AN: 1461502 Hom.: 82 Cov.: 31 AF XY: 0.00921 AC XY: 6698 AN XY: 727044

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.00340

Gnomad4 ASJ exome AF: 0.00563

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000603

Gnomad4 FIN exome AF: 0.0152

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00785

GnomAD4 genome AF: 0.00717 AC: 1092 AN: 152268 Hom.: 11 Cov.: 32 AF XY: 0.00729 AC XY: 543 AN XY: 74452

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00530

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0167

Gnomad4 NFE AF: 0.0107

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00992 Hom.: 10

Bravo AF: 0.00635

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00159 AC: 5

ESP6500EA AF: 0.0120 AC: 86

ExAC AF: 0.00792 AC: 955

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.0108

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	PCDH15: BP4, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Val1508Met in Exon 35B of PCDH15: This variant is not expected to have clinical significance because it has been identified in 1.2% (63/5446) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs41274622). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0074	T;.;.;.;.;T;.;.;T;.;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.87	D;T;D;D;D;D;D;T;T;T;T
MetaRNN	Benign	0.0087	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	D;D;D;N;N;N;N;N
REVEL	Benign	0.094
Sift4G	Benign	0.40	T;.;T;T;T;T;T;T;T;T;T
Vest4		0.41
MVP		0.46
ClinPred		0.069	T
GERP RS		4.2

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: rs41274622; hg19: chr10-55570347; COSMIC: COSV64706061;