rs1205783002
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP5_Moderate
The NM_000426.4(LAMA2):βc.8180_8181delβ(p.Ile2727SerfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.0000034 ( 0 hom. )
Consequence
LAMA2
NM_000426.4 frameshift
NM_000426.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.989
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 10 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 6-129492417-AAT-A is Pathogenic according to our data. Variant chr6-129492417-AAT-A is described in ClinVar as [Pathogenic]. Clinvar id is 477512.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LAMA2 | NM_000426.4 | c.8180_8181del | p.Ile2727SerfsTer5 | frameshift_variant | 58/65 | ENST00000421865.3 | NP_000417.3 | |
LAMA2 | NM_001079823.2 | c.8168_8169del | p.Ile2723SerfsTer5 | frameshift_variant | 57/64 | NP_001073291.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LAMA2 | ENST00000421865.3 | c.8180_8181del | p.Ile2727SerfsTer5 | frameshift_variant | 58/65 | 5 | NM_000426.4 | ENSP00000400365 | ||
ENST00000665046.1 | n.975+10186_975+10187del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461830Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727216
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74358
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
LAMA2-related muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 15, 2022 | This sequence change creates a premature translational stop signal (p.Ile2727Serfs*5) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 477512). This variant has not been reported in the literature in individuals affected with LAMA2-related conditions. This variant is not present in population databases (gnomAD no frequency). - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at