chr15-28114646-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate
The NM_004667.6(HERC2):c.13879C>T(p.Arg4627Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_004667.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HERC2 | NM_004667.6 | c.13879C>T | p.Arg4627Cys | missense_variant | 90/93 | ENST00000261609.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HERC2 | ENST00000261609.13 | c.13879C>T | p.Arg4627Cys | missense_variant | 90/93 | 1 | NM_004667.6 | P1 | |
HERC2 | ENST00000566635.5 | n.1004C>T | non_coding_transcript_exon_variant | 4/7 | 1 | ||||
HERC2 | ENST00000650509.1 | c.*993C>T | 3_prime_UTR_variant, NMD_transcript_variant | 36/39 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152042Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251348Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135850
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461840Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5AN XY: 727214
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152160Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74358
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 10, 2023 | The c.13879C>T (p.R4627C) alteration is located in exon 90 (coding exon 89) of the HERC2 gene. This alteration results from a C to T substitution at nucleotide position 13879, causing the arginine (R) at amino acid position 4627 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 11, 2019 | This sequence change replaces arginine with cysteine at codon 4627 of the HERC2 protein (p.Arg4627Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs748944643, ExAC 0.02%). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with HERC2-related disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at