chr10-53806748-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001384140.1(PCDH15):ā€‹c.5054T>Cā€‹(p.Val1685Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000089 ( 0 hom. )

Consequence

PCDH15
NM_001384140.1 missense

Scores

16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.0820
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.08872473).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PCDH15NM_001384140.1 linkuse as main transcriptc.5054T>C p.Val1685Ala missense_variant 38/38 ENST00000644397.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PCDH15ENST00000644397.2 linkuse as main transcriptc.5054T>C p.Val1685Ala missense_variant 38/38 NM_001384140.1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152000
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
248692
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135118
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000869
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:
0.00
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461634
Hom.:
0
Cov.:
33
AF XY:
0.0000110
AC XY:
8
AN XY:
727100
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000134
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:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152000
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74264
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000830
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Usher syndrome type 1F Uncertain:2
Uncertain significance, criteria provided, single submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardJan 24, 2023The p.Val1685Ala variant in PCDH15 has been reported in 1 individual, in the homozygous state, with Usher syndrome type 1F (PMID: 22952768) and has been identified in 0.008% (3/35362) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs140716525). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 554592) and has been interpreted as a variant of uncertain significance by Counsyl. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Val1685Ala variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PM3_supporting, BP4 (Richards 2015). -
Uncertain significance, criteria provided, single submitterclinical testingCounsylOct 26, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
0.064
DANN
Benign
0.65
DEOGEN2
Benign
0.0021
T;.;.;.;.;T;.;.
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.052
N
LIST_S2
Benign
0.44
T;T;T;T;T;T;T;T
M_CAP
Benign
0.0077
T
MetaRNN
Benign
0.089
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.97
T
MutationTaster
Benign
1.0
N;N
PROVEAN
Benign
0.20
N;.;.;.;.;.;.;.
REVEL
Benign
0.094
Sift
Benign
0.16
T;.;.;.;.;.;.;.
Sift4G
Benign
0.72
T;.;T;T;T;T;T;T
Vest4
0.032
MutPred
0.20
.;.;Loss of methylation at K1627 (P = 0.0358);.;.;.;.;.;
MVP
0.092
ClinPred
0.086
T
GERP RS
-12

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs755487351; hg19: chr10-55566508; API