rs143827620

Positions:

• chr10-54195732-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001384140.1(PCDH15):​c.1256A>G​(p.Asn419Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000886 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.45

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039476007).
• BP6: Variant 10-54195732-T-C is Benign according to our data. Variant chr10-54195732-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164927.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.1256A>G	p.Asn419Ser	missense_variant	11/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.1256A>G	p.Asn419Ser	missense_variant	11/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.1256A>G	p.Asn419Ser	missense_variant	11/33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.1256A>G	p.Asn419Ser	missense_variant	11/38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000957

GnomAD3 exomes AF: 0.0000756 AC: 19 AN: 251456 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135900

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000520 AC: 76 AN: 1461788 Hom.: 0 Cov.: 33 AF XY: 0.0000330 AC XY: 24 AN XY: 727196

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.0000671

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: 0.00

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74448

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.000196

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: 0.000947

Alfa AF: 0.0000881 Hom.: 0

Bravo AF: 0.000521

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

Usher syndrome type 1 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 29, 2014

p.Asn419Ser variant in exon 11 of PCDH15: This variant is not expected to have c linical significance because it has been identified in 0.136% (6/4406) of Afric an American chromosomes by the NHLBI Exome Sequencing Project, and in 1.639% (2/ 122) of African American chromosomes and in 0.568% (1/176) of Nigerian chromosom es by the 1000 Genomes Project (http://evs.gs.washington.edu/EVS/; dbSNP rs14382 7620). In addtion, asparaginine (Asn) at position 419 is not well conserved in m ammals or evolutionarily distant species with many fish carrying a serine (Ser) at this position and computational prediction tools do not suggest a high likeli hood of impact to the protein. which supports that variants at this position may be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.022	T;.;.;.;.;T;.;T;.;T;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen	Benign	-0.0062
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.039	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.3	.;.;.;.;L;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;L;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.1	N;.;.;.;.;.;N;.;N;N;.;N;N;.;N;.;.;N;N;N;N;N;N;N
REVEL	Benign	0.073
Sift	Benign	0.12	T;.;.;.;.;.;T;.;T;T;.;T;T;.;T;.;.;T;T;T;T;T;T;T
Sift4G	Benign	0.27	T;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.73, 0.56, 1.0, 0.097, 0.38, 0.15	.;.;.;.;.;.;.;.;.;.;.;.;P;.;P;.;.;P;D;D;.;B;B;B
Vest4		0.26
MVP		0.69
MPC		0.031
ClinPred		0.037	T
GERP RS		5.1
Varity_R		0.12
gMVP		0.26

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: rs143827620; hg19: chr10-55955492;