rs61731363

Positions:

• chr10-54022983-A-G

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.2435T>C​(p.Ile812Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0006 in 1,613,974 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (2 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 9.25

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=0.012396306).
• BP6: Variant 10-54022983-A-G is Benign according to our data. Variant chr10-54022983-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 178628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54022983-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00315 (479/152230) while in subpopulation AFR AF= 0.0109 (453/41566). AF 95% confidence interval is 0.0101. There are 2 homozygotes in gnomad4. There are 214 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.2435T>C	p.Ile812Thr	missense_variant	19/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.2435T>C	p.Ile812Thr	missense_variant	19/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.2435T>C	p.Ile812Thr	missense_variant	19/33	1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.2435T>C	p.Ile812Thr	missense_variant	19/38		NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes AF: 0.00309 AC: 470 AN: 152112 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

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: 0.00

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.000696 AC: 175 AN: 251336 Hom.: 0 AF XY: 0.000545 AC XY: 74 AN XY: 135840

Gnomad AFR exome AF: 0.00947

Gnomad AMR exome AF: 0.000491

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: 0.00000880

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000335 AC: 490 AN: 1461744 Hom.: 2 Cov.: 31 AF XY: 0.000278 AC XY: 202 AN XY: 727166

Gnomad4 AFR exome AF: 0.0114

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00315 AC: 479 AN: 152230 Hom.: 2 Cov.: 32 AF XY: 0.00288 AC XY: 214 AN XY: 74428

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.000534 Hom.: 0

Bravo AF: 0.00356

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000898 AC: 109

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:8

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2021	This variant is associated with the following publications: (PMID: 27766948) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	PCDH15: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ile812Thr in Exon 19 of PCDH15: This variant is not expected to have clinical si gnificance because it has been identified in 0.7% (26/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs61731363). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 19, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 12, 2022	Variant summary: PCDH15 c.2435T>C (p.Ile812Thr) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0031 in 152112 control chromosomes, predominantly at a frequency of 0.011 within the African or African-American subpopulation in the gnomAD v3 database (genomes data), including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=4) and benign (n=2). Based on the evidence outlined above, the variant was classified as benign. -

Usher syndrome type 1F Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Jan 09, 2017

- -

Usher syndrome type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	Uncertain	0.42
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T;.;.;.;.;T;T;T;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.012	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.4	.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.0	.;.;.;D;.;.;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D;D
REVEL	Uncertain	0.49
Sift	Benign	0.044	.;.;.;D;.;.;.;D;.;T;D;.;D;.;.;D;T;T;.;D;D;D
Sift4G	Uncertain	0.0020	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.95, 0.99, 0.97, 0.99, 1.0, 0.98	.;.;.;.;.;.;.;.;.;.;P;.;D;.;.;D;D;D;.;D;D;D
Vest4		0.88
MVP		0.81
MPC		0.18
ClinPred		0.025	T
GERP RS		5.7
Varity_R		0.24
gMVP		0.65

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: rs61731363; hg19: chr10-55782743;