6-129514385-G-C
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000426.4(LAMA2):āc.9001G>Cā(p.Val3001Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,613,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00013 ( 0 hom., cov: 33)
Exomes š: 0.00017 ( 0 hom. )
Consequence
LAMA2
NM_000426.4 missense
NM_000426.4 missense
Scores
2
7
4
Clinical Significance
Conservation
PhyloP100: 7.83
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 Likely_benign. Variant got -2 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.14247555).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA2 | NM_000426.4 | c.9001G>C | p.Val3001Leu | missense_variant | 64/65 | ENST00000421865.3 | |
LOC102723409 | XR_001743860.2 | n.12102+8092C>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA2 | ENST00000421865.3 | c.9001G>C | p.Val3001Leu | missense_variant | 64/65 | 5 | NM_000426.4 | ||
ENST00000665046.1 | n.788+8092C>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152148Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000151 AC: 38AN: 251088Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135682
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GnomAD4 exome AF: 0.000171 AC: 250AN: 1460756Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 108AN XY: 726788
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GnomAD4 genome AF: 0.000131 AC: 20AN: 152264Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74444
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 14, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 16, 2017 | The V3001L variant in the LAMA2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V3001L variant is observed in 12/66576 (0.018%) alleles from individuals of non-Finnish European background, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V3001L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V3001L as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2017 | - - |
Congenital muscular dystrophy due to partial LAMA2 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 02, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
LAMA2-related muscular dystrophy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
T
MutationTaster
Benign
D
PrimateAI
Uncertain
T
Polyphen
0.97
.;.;D
Vest4
MutPred
0.64
.;.;Loss of catalytic residue at M2998 (P = 0.1036);
MVP
MPC
0.12
ClinPred
T
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gMVP
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at