rs121913574
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5
The NM_000426.4(LAMA2):c.1580G>A(p.Cys527Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,432 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
LAMA2
NM_000426.4 missense
NM_000426.4 missense
Scores
13
3
2
Clinical Significance
Conservation
PhyloP100: 8.65
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_pathogenic. Variant got 7 ACMG points.
PM1
In a domain Laminin EGF-like 5; first part (size 9) in uniprot entity LAMA2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000426.4
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 6-129190317-G-A is Pathogenic according to our data. Variant chr6-129190317-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14298.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr6-129190317-G-A is described in Lovd as [Pathogenic]. Variant chr6-129190317-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA2 | NM_000426.4 | c.1580G>A | p.Cys527Tyr | missense_variant | 11/65 | ENST00000421865.3 | |
LAMA2 | NM_001079823.2 | c.1580G>A | p.Cys527Tyr | missense_variant | 11/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA2 | ENST00000421865.3 | c.1580G>A | p.Cys527Tyr | missense_variant | 11/65 | 5 | NM_000426.4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250784Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135632
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461252Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726928
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74340
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
LAMA2-related muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 527 of the LAMA2 protein (p.Cys527Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with features of congenital muscular dystrophy and congenital muscular dystrophy (PMID: 12552556, 23326386; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 14298). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LAMA2 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Congenital muscular dystrophy due to partial LAMA2 deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2003 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 05, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
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
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;H
MutationTaster
Benign
A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
.;.;D
REVEL
Pathogenic
Sift
Pathogenic
.;.;D
Polyphen
1.0
.;.;D
Vest4
MutPred
Loss of stability (P = 0.0663);Loss of stability (P = 0.0663);Loss of stability (P = 0.0663);
MVP
MPC
0.62
ClinPred
D
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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