rs535635043
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000426.4(LAMA2):c.363C>A(p.Tyr121Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000437 in 1,601,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000426.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA2 | NM_000426.4 | c.363C>A | p.Tyr121Ter | stop_gained | 3/65 | ENST00000421865.3 | |
LAMA2 | NM_001079823.2 | c.363C>A | p.Tyr121Ter | stop_gained | 3/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA2 | ENST00000421865.3 | c.363C>A | p.Tyr121Ter | stop_gained | 3/65 | 5 | NM_000426.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251358Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135850
GnomAD4 exome AF: 0.00000345 AC: 5AN: 1448792Hom.: 0 Cov.: 27 AF XY: 0.00000277 AC XY: 2AN XY: 721714
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152290Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74466
ClinVar
Submissions by phenotype
Merosin deficient congenital muscular dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 14, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 01, 2017 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2021 | Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 30301903, 31589614, 32266982, 18700894, 24611677) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 30, 2021 | - - |
LAMA2-related muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 11, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 551699). This premature translational stop signal has been observed in individuals with congenital muscular dystrophy (PMID: 18700894, 24611677, 30055037, 30301903). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs535635043, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Tyr121*) in the LAMA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMA2 are known to be pathogenic (PMID: 18700894, 32904964). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at