rs191899712
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1
The NM_000426.4(LAMA2):c.149C>T(p.Ala50Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000426.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251486Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135920
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461730Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727192
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152254Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74438
ClinVar
Submissions by phenotype
not provided Uncertain:2
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In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Merosin deficient congenital muscular dystrophy Pathogenic:1
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not specified Uncertain:1
Variant summary: LAMA2 c.149C>T (p.Ala50Val) results in a non-conservative amino acid change located in the Laminin, N-terminal domain (IPR008211) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251486 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LAMA2 causing Laminin Alpha 2-Related Dystrophy (4e-05 vs 0.0022), allowing no conclusion about variant significance. c.149C>T has been reported in the literature in at least one compound heterozygous individual affected with muscular dystrophy, limb-girdle (e.g. Barbosa-Gouveia_2022). These data do not allow sufficient evidence to provide any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35628876, 29773157). ClinVar contains an entry for this variant (Variation ID: 570290). Based on the evidence outlined above, the variant was classified as uncertain significance. -
LAMA2-related muscular dystrophy Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at