rs61731907
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_002180.3(IGHMBP2):c.1422C>A(p.Asp474Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,611,576 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002180.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000342 AC: 52AN: 152002Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000462 AC: 114AN: 246930Hom.: 0 AF XY: 0.000410 AC XY: 55AN XY: 134010
GnomAD4 exome AF: 0.000210 AC: 307AN: 1459456Hom.: 2 Cov.: 31 AF XY: 0.000209 AC XY: 152AN XY: 726020
GnomAD4 genome AF: 0.000342 AC: 52AN: 152120Hom.: 0 Cov.: 33 AF XY: 0.000323 AC XY: 24AN XY: 74360
ClinVar
Submissions by phenotype
not provided Uncertain:3
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Reported previously in the heterozygous state in a patient with Charcot-Marie-Tooth disease; however, further clinical and segregation information were not provided (Volodarsky et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32376792, 22965130, 25439726, 24388491) -
Charcot-Marie-Tooth disease Uncertain:1
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Autosomal recessive distal spinal muscular atrophy 1 Uncertain:1
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. -
Inborn genetic diseases Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at