rs146745502

chr10-53827426-G-Cchr10-53827426-G-T

Variant summary

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

The NM_033056.4(PCDH15):c.4334C>G(p.Ala1445Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000544 in 1,613,180 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1445A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00064 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (11 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.19

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=0.0056104064).
• BP6: Variant 10-53827426-G-C is Benign according to our data. Variant chr10-53827426-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 46480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000534 (780/1460842) while in subpopulation AMR AF= 0.0163 (726/44658). AF 95% confidence interval is 0.0153. There are 11 homozygotes in gnomad4_exome. There are 325 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.4334C>G	p.Ala1445Gly	missense_variant	32/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.4334C>G	p.Ala1445Gly	missense_variant	32/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.4334C>G	p.Ala1445Gly	missense_variant	32/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.4334C>G	p.Ala1445Gly	missense_variant	32/38		NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152220 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00451

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00267 AC: 663 AN: 248074 Hom.: 12 AF XY: 0.00194 AC XY: 261 AN XY: 134408

Gnomad AFR exome AF: 0.000375

Gnomad AMR exome AF: 0.0187

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000901

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000534 AC: 780 AN: 1460842 Hom.: 11 Cov.: 31 AF XY: 0.000447 AC XY: 325 AN XY: 726582

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0163

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000643 AC: 98 AN: 152338 Hom.: 2 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74496

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.00161

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00221 AC: 268

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 05, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 04, 2016

p.Ala1445Gly in exon 32 of PCDH15: This variant is not expected to have clinical significance because it has been identified in 2.3% (261/11556) of Latino chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs146745502). -

PCDH15-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Usher syndrome type 1F Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Usher syndrome type 1 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.014	T;.;.;.;.;T;.;T;T;T;.;.;T;.;T;.;.;.;.;.;.;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0056	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.58	T
REVEL	Benign	0.065
Sift4G	Benign	0.40	T;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.43, 0.29, 0.66	.;.;.;.;.;.;.;.;.;.;.;.;.;B;.;.;B;B;B;.;P;B
Vest4		0.42
MVP		0.75
MPC		0.042
ClinPred		0.014	T
GERP RS		3.8
Varity_R		0.070
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs146745502; hg19: chr10-55587186;