rs191736346

chr10-53822123-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_033056.4(PCDH15):c.5603C>T(p.Thr1868Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000698 in 1,597,172 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1868T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (2 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 2.86

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042761564).
• BP6: Variant 10-53822123-G-A is Benign according to our data. Variant chr10-53822123-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46506.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5}. Variant chr10-53822123-G-A is described in Lovd as [Benign]. Variant chr10-53822123-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00386 (559/144692) while in subpopulation AFR AF= 0.015 (519/34708). AF 95% confidence interval is 0.0139. There are 3 homozygotes in gnomad4. There are 257 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.5603C>T	p.Thr1868Met	missense_variant	33/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.4368-1893C>T		intron_variant		ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.5603C>T	p.Thr1868Met	missense_variant	33/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.4368-1893C>T		intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.00386 AC: 558 AN: 144618 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00189

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00250

GnomAD3 exomes AF: 0.000978 AC: 246 AN: 251408 Hom.: 3 AF XY: 0.000670 AC XY: 91 AN XY: 135874

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000383 AC: 556 AN: 1452480 Hom.: 2 Cov.: 32 AF XY: 0.000321 AC XY: 232 AN XY: 723090

Gnomad4 AFR exome AF: 0.0134

Gnomad4 AMR exome AF: 0.00122

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000522

Gnomad4 OTH exome AF: 0.000790

GnomAD4 genome AF: 0.00386 AC: 559 AN: 144692 Hom.: 3 Cov.: 32 AF XY: 0.00363 AC XY: 257 AN XY: 70794

Gnomad4 AFR AF: 0.0150

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00247

Alfa AF: 0.000426 Hom.: 2

Bravo AF: 0.00413

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00128 AC: 153

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2017	Thr1868Met in exon 33 of PCDH15: This variant is not expected to have clinical s ignificance because it has been identified in 1.5% (132/8652) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs191736346). -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2019	This variant is associated with the following publications: (PMID: 26969326) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Usher syndrome type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	15
Dann	Uncertain	0.98
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0043	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.040	N;.;.;N;N;N;.;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0040	D;.;.;D;D;D;.;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D
Polyphen		0.88	P;.;.;P;P;P;.;P;P
Vest4		0.12
MVP		0.74
MPC		0.028
ClinPred		0.017	T
GERP RS		2.7
Varity_R		0.037
gMVP		0.22

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: rs191736346; hg19: chr10-55581883; COSMIC: COSV57288412; COSMIC: COSV57288412;