rs139915181

Positions:

• chr10-53822993-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.4733T>C​(p.Val1578Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000274 in 1,613,942 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. V1578V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.52

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=0.0031734705).
• BP6: Variant 10-53822993-A-G is Benign according to our data. Variant chr10-53822993-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 178520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53822993-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00156 (238/152154) while in subpopulation AFR AF= 0.00556 (231/41526). AF 95% confidence interval is 0.00497. There are 2 homozygotes in gnomad4. There are 96 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	UniProt
PCDH15	NM_033056.4	c.4733T>C	p.Val1578Ala	missense_variant	33/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.4368-2763T>C		intron_variant		ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.4733T>C	p.Val1578Ala	missense_variant	33/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.4368-2763T>C		intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 237 AN: 152036 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000310 AC: 78 AN: 251366 Hom.: 0 AF XY: 0.000272 AC XY: 37 AN XY: 135858

Gnomad AFR exome AF: 0.00443

Gnomad AMR exome AF: 0.000116

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000140 AC: 204 AN: 1461788 Hom.: 1 Cov.: 33 AF XY: 0.000121 AC XY: 88 AN XY: 727200

Gnomad4 AFR exome AF: 0.00532

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.00156 AC: 238 AN: 152154 Hom.: 2 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74404

Gnomad4 AFR AF: 0.00556

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000295 Hom.: 0

Bravo AF: 0.00163

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000461 AC: 56

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 14, 2017	The c.4733T>C; p.Val1578Ala variant (rs139915181) has not been reported in the medical literature, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.5 percent in the African population (identified on 122 out of 24,028 chromosomes), and reported to ClinVar as likely benign (Variation ID: 178520). The valine at position 1578 is weakly conserved considering 12 species (Alamut v2.9.0) and computational analyses of the p.Val1578Ala variant on protein structure and function indicate a neutral effect (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Altogether the p.Val1578Ala variant is likely to be benign. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Val1578Ala in Exon 33 of PCDH15: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (13/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs139915181). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.97
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.78	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.0032	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.51	N;.;.;N;N;N;.;N;N
REVEL	Benign	0.068
Sift	Benign	0.086	T;.;.;T;T;T;.;T;T
Sift4G	Benign	0.62	T;T;T;T;T;T;T;T;T
Polyphen		0.0020	B;.;.;B;B;B;.;B;B
Vest4		0.029
MVP		0.54
MPC		0.031
ClinPred		0.0081	T
GERP RS		2.0
Varity_R		0.045
gMVP		0.13

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: rs139915181; hg19: chr10-55582753;