rs192117840
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_001164507.2(NEB):c.3184A>G(p.Lys1062Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,613,874 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). Synonymous variant affecting the same amino acid position (i.e. K1062K) has been classified as Likely benign.
Frequency
Consequence
NM_001164507.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.3184A>G | p.Lys1062Glu | missense_variant | 32/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.3184A>G | p.Lys1062Glu | missense_variant | 32/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.3184A>G | p.Lys1062Glu | missense_variant | 32/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.3184A>G | p.Lys1062Glu | missense_variant | 32/182 | 5 | NM_001164507.2 | A2 | |
NEB | ENST00000409198.5 | c.3184A>G | p.Lys1062Glu | missense_variant | 32/150 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000671 AC: 102AN: 152100Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000144 AC: 36AN: 249240Hom.: 0 AF XY: 0.000111 AC XY: 15AN XY: 135218
GnomAD4 exome AF: 0.0000787 AC: 115AN: 1461656Hom.: 0 Cov.: 33 AF XY: 0.0000811 AC XY: 59AN XY: 727112
GnomAD4 genome ? AF: 0.000670 AC: 102AN: 152218Hom.: 0 Cov.: 31 AF XY: 0.000685 AC XY: 51AN XY: 74424
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 23, 2023 | Variant summary: NEB c.3184A>G (p.Lys1062Glu) results in a 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 0.00021 in 280622 control chromosomes (gnomAD), predominantly at a frequency of 0.0019 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in NEB causing Nemaline Myopathy 2 (0.00021 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3184A>G in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely benign, and one classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 21, 2021 | The c.3184A>G (p.K1062E) alteration is located in exon 32 (coding exon 30) of the NEB gene. This alteration results from a A to G substitution at nucleotide position 3184, causing the lysine (K) at amino acid position 1062 to be replaced by a glutamic acid (E). 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 | Athena Diagnostics | Jul 13, 2023 | Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. - |
NEB-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 01, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Nemaline myopathy 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at