6-129098213-C-G
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1
The NM_000426.4(LAMA2):āc.437C>Gā(p.Ser146Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,613,730 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00014 ( 0 hom., cov: 32)
Exomes š: 0.00014 ( 0 hom. )
Consequence
LAMA2
NM_000426.4 missense
NM_000426.4 missense
Scores
6
8
4
Clinical Significance
Conservation
PhyloP100: 2.06
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 Uncertain_significance. Variant got 2 ACMG points.
PM1
In a domain Laminin N-terminal (size 251) in uniprot entity LAMA2_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) in NM_000426.4
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000145 AC: 22AN: 152086Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000183 AC: 46AN: 251462Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135910
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GnomAD4 exome AF: 0.000139 AC: 203AN: 1461526Hom.: 0 Cov.: 31 AF XY: 0.000160 AC XY: 116AN XY: 727100
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GnomAD4 genome AF: 0.000145 AC: 22AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74442
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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 | GeneDx | Apr 15, 2021 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 15, 2024 | PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 21, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 17, 2024 | Variant summary: LAMA2 c.437C>G (p.Ser146Cys) results in a non-conservative amino acid change located in the Laminin, N-terminal domain (IPR008211) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251462 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LAMA2 causing Laminin Alpha 2-Related Dystrophy (0.00018 vs 0.0022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.437C>G in individuals affected with Laminin Alpha 2-Related Dystrophy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 543838). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
LAMA2-related muscular dystrophy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;T;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
.;.;H
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;.;D
REVEL
Pathogenic
Sift
Uncertain
.;.;D
Polyphen
1.0
.;.;D
Vest4
MVP
MPC
0.47
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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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