rs527250558
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001164507.2(NEB):c.19966C>T(p.Arg6656Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000698 in 1,589,280 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6656H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001164507.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.19966C>T | p.Arg6656Cys | missense_variant | 130/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.19966C>T | p.Arg6656Cys | missense_variant | 130/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.19966C>T | p.Arg6656Cys | missense_variant | 130/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.19966C>T | p.Arg6656Cys | missense_variant | 130/182 | 5 | NM_001164507.2 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000952 AC: 20AN: 210040Hom.: 0 AF XY: 0.000116 AC XY: 13AN XY: 112392
GnomAD4 exome AF: 0.0000640 AC: 92AN: 1437000Hom.: 0 Cov.: 30 AF XY: 0.0000702 AC XY: 50AN XY: 712096
GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152280Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74448
ClinVar
Submissions by phenotype
Nemaline myopathy 2 Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 07, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 02, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 25, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 31, 2022 | Variant summary: NEB c.19966C>T (p.Arg6656Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 210040 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in NEB causing Nemaline Myopathy 2 (9.5e-05 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.19966C>T in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at