rs148168494
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_153676.4(USH1C):āc.2194A>Gā(p.Lys732Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,613,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00012 ( 0 hom., cov: 32)
Exomes š: 0.0000075 ( 0 hom. )
Consequence
USH1C
NM_153676.4 missense
NM_153676.4 missense
Scores
2
7
10
Clinical Significance
Conservation
PhyloP100: 5.85
Genes affected
USH1C (HGNC:12597): (USH1 protein network component harmonin) This gene encodes a scaffold protein that functions in the assembly of Usher protein complexes. The protein contains PDZ domains, a coiled-coil region with a bipartite nuclear localization signal and a PEST degradation sequence. Defects in this gene are the cause of Usher syndrome type 1C and non-syndromic sensorineural deafness autosomal recessive type 18. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.27548912).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH1C | NM_153676.4 | c.2194A>G | p.Lys732Glu | missense_variant | 21/27 | ENST00000005226.12 | |
USH1C | NM_005709.4 | c.1294A>G | p.Lys432Glu | missense_variant | 16/21 | ENST00000318024.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH1C | ENST00000005226.12 | c.2194A>G | p.Lys732Glu | missense_variant | 21/27 | 5 | NM_153676.4 | ||
USH1C | ENST00000318024.9 | c.1294A>G | p.Lys432Glu | missense_variant | 16/21 | 1 | NM_005709.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152030Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000319 AC: 8AN: 251094Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135668
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461552Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727078
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GnomAD4 genome AF: 0.000125 AC: 19AN: 152030Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74250
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 08, 2011 | Variant classified as Uncertain Significance - Favor Benign. The Lys732Glu varia nt in USH1C has not been reported in the literature nor previously identified by our laboratory. However, this variant was observed in a broad population (dbSN P rs148168494) suggesting it could occur with reasonable frequency in the genera l population. Computational analyses (biochemical amino acid properties, homolog y, PolyPhen2, SIFT, AlignGVGD) do not provide strong support for or against path ogenicity. In summary, the clinical significance of this variant cannot be deter mined at this time; however, based on identification of this variant in this ind ividual who has another cause for their clinical features and in dbSNP we would lean towards a more likely benign role. - |
Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 24, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 03, 2022 | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 432 of the USH1C protein (p.Lys432Glu). This variant is present in population databases (rs148168494, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with USH1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 47994). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Usher syndrome type 1C Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 08, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N
REVEL
Benign
Sift
Pathogenic
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
P;.;P;.
Vest4
MVP
MPC
0.45
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at