rs398123385
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000426.4(LAMA2):βc.7279_7280delβ(p.Leu2427ValfsTer17) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,611,290 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.0000014 ( 0 hom. )
Consequence
LAMA2
NM_000426.4 frameshift
NM_000426.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.38
Genes affected
LAMA2 (HGNC:6482): (laminin subunit alpha 2) Laminin, an extracellular protein, is a major component of the basement membrane. It is thought to mediate the attachment, migration, and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components. It is composed of three subunits, alpha, beta, and gamma, which are bound to each other by disulfide bonds into a cross-shaped molecule. This gene encodes the alpha 2 chain, which constitutes one of the subunits of laminin 2 (merosin) and laminin 4 (s-merosin). Mutations in this gene have been identified as the cause of congenital merosin-deficient muscular dystrophy. Two transcript variants encoding different proteins have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-129465265-ACT-A is Pathogenic according to our data. Variant chr6-129465265-ACT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA2 | NM_000426.4 | c.7279_7280del | p.Leu2427ValfsTer17 | frameshift_variant | 51/65 | ENST00000421865.3 | |
LAMA2 | NM_001079823.2 | c.7279_7280del | p.Leu2427ValfsTer17 | frameshift_variant | 51/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA2 | ENST00000421865.3 | c.7279_7280del | p.Leu2427ValfsTer17 | frameshift_variant | 51/65 | 5 | NM_000426.4 | ||
ENST00000665046.1 | n.976-24015_976-24014del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151930Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459360Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726018
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 151930Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74192
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2022 | Observed with a nonsense variant in an individual with congenital hypotonia and peripheral demyelinating neuropathy, however it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Stehlikova et al., 2016); Frameshift 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27447704) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 08, 2013 | - - |
Merosin deficient congenital muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 03, 2023 | - - |
LAMA2-related muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 19, 2021 | For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individuals with autosomal recessive congenital muscular dystrophy (PMID: 27447704; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu2427Valfs*17) 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). - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at