10-53903293-C-T

Variant names:

• chr10-53903293-C-T
• rs149478475
• NM_033056.4:c.3451G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033056.4(PCDH15):​c.3451G>A​(p.Gly1151Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00035 in 1,613,102 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. G1151G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.07
• Publications: 15 publications found

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]

PCDH15 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 23

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, PROVEAN [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.009842426).
• BP6: Variant 10-53903293-C-T is Benign according to our data. Variant chr10-53903293-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 179960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000526 (80/152184) while in subpopulation EAS AF = 0.0143 (74/5174). AF 95% confidence interval is 0.0117. There are 0 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.3451G>A	p.Gly1151Arg	missense_variant	Exon 26 of 33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.3451G>A	p.Gly1151Arg	missense_variant	Exon 26 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.3451G>A	p.Gly1151Arg	missense_variant	Exon 26 of 33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.3451G>A	p.Gly1151Arg	missense_variant	Exon 26 of 38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152066 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0143

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00131 AC: 329 AN: 250984 AF XY: 0.00128

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0169

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000331 AC: 484 AN: 1460918 Hom.: 2 Cov.: 31 AF XY: 0.000319 AC XY: 232 AN XY: 726790

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.000112 AC: 5 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.0104 AC: 413 AN: 39626

South Asian (SAS) AF: 0.000441 AC: 38 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53202

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111454

Other (OTH) AF: 0.000398 AC: 24 AN: 60360

GnomAD4 genome AF: 0.000526 AC: 80 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.000726 AC XY: 54 AN XY: 74402

African (AFR) AF: 0.00 AC: 0 AN: 41556

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0143 AC: 74 AN: 5174

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67972

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000417 Hom.: 1

Bravo AF: 0.000710

ExAC AF: 0.00126 AC: 153

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 02, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Jan 12, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gly1151Arg in exon 26 of PCDH15: This variant is not expected to have clinical significance because it has been identified in 1.7% (322/18942) of East Asian c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org/; dbSNP rs149478475). -

Jul 12, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PCDH15 c.3451G>A (p.Gly1151Arg) 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 0.0013 in 250984 control chromosomes, predominantly at a frequency of 0.017 within the East Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 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 East Asian 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=3) and benign (n=3). Based on the evidence outlined above, the variant was classified as benign. -

Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F Benign:1

Jul 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1F Benign:1

Apr 16, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Usher syndrome type 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.073	T;.;.;.;.;T;T;T;T;.;.;T;.;T;.;.;.;.;.;.;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0098	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.073	T
MutationAssessor	Pathogenic	3.0	.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;M
PhyloP100		7.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.5	.;.;.;.;.;.;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0030	.;.;.;.;.;.;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D
Sift4G	Pathogenic	0.0010	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D
Vest4		0.92
MutPred		0.73		Gain of MoRF binding (P = 0.0047);Gain of MoRF binding (P = 0.0047);.;Gain of MoRF binding (P = 0.0047);Gain of MoRF binding (P = 0.0047);.;Gain of MoRF binding (P = 0.0047);.;.;.;Gain of MoRF binding (P = 0.0047);.;.;.;.;Gain of MoRF binding (P = 0.0047);Gain of MoRF binding (P = 0.0047);.;.;.;Gain of MoRF binding (P = 0.0047);
MVP		0.90
MPC		0.24
ClinPred		0.094	T
GERP RS		5.0
Varity_R		0.44
gMVP		0.88
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs149478475; hg19: chr10-55663053; COSMIC: COSV100230592;