6-129316089-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000426.4(LAMA2):c.3976C>T(p.Arg1326*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000471 in 1,611,900 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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LAMA2 | ENST00000421865.3 | c.3976C>T | p.Arg1326* | stop_gained | Exon 27 of 65 | 5 | NM_000426.4 | ENSP00000400365.2 | ||
LAMA2 | ENST00000618192.5 | c.4240C>T | p.Arg1414* | stop_gained | Exon 28 of 66 | 5 | ENSP00000480802.2 | |||
LAMA2 | ENST00000617695.5 | c.3976C>T | p.Arg1326* | stop_gained | Exon 27 of 64 | 5 | ENSP00000481744.2 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 151964Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251222Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135796
GnomAD4 exome AF: 0.0000486 AC: 71AN: 1459936Hom.: 0 Cov.: 30 AF XY: 0.0000537 AC XY: 39AN XY: 726420
GnomAD4 genome AF: 0.0000329 AC: 5AN: 151964Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74212
ClinVar
Submissions by phenotype
not provided Pathogenic:5
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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 (gnomAD); This variant is associated with the following publications: (PMID: 20207543, 25525159, 18700894, 11938437, 25663498, 32403337, 32266982, 32528171, 30055037, 32906206, 33726816, Vercellino_2022, 34503567) -
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PM2, PM3_very_strong, PVS1 -
Merosin deficient congenital muscular dystrophy Pathogenic:2
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LAMA2-related muscular dystrophy Pathogenic:2
This sequence change creates a premature translational stop signal (p.Arg1326*) 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). This variant is present in population databases (rs398123373, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with LAMA2-related muscular dystrophy (PMID: 18700894, 30055037). ClinVar contains an entry for this variant (Variation ID: 92956). For these reasons, this variant has been classified as Pathogenic. -
Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with LAMA2-related muscular dystrophy (MONDO:0100228). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (76 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported nine times as pathogenic in ClinVar by clinical laboratories. This variant has been observed in individuals with LAMA2-related muscular dystrophy (PMIDs: 34281576, 37182895). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 Pathogenic:1
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Muscular dystrophy, limb-girdle, autosomal recessive 23 Pathogenic:1
ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM3 moderated -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at