6-129280122-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_000426.4(LAMA2):c.2512G>A(p.Gly838Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,611,520 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G838E) has been classified as Benign.
Frequency
Consequence
NM_000426.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA2 | NM_000426.4 | c.2512G>A | p.Gly838Arg | missense_variant | 18/65 | ENST00000421865.3 | |
LAMA2 | NM_001079823.2 | c.2512G>A | p.Gly838Arg | missense_variant | 18/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA2 | ENST00000421865.3 | c.2512G>A | p.Gly838Arg | missense_variant | 18/65 | 5 | NM_000426.4 | ||
LAMA2 | ENST00000618192.5 | c.2512G>A | p.Gly838Arg | missense_variant | 18/66 | 5 | P1 | ||
LAMA2 | ENST00000617695.5 | c.2512G>A | p.Gly838Arg | missense_variant | 18/64 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152046Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251224Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135770
GnomAD4 exome AF: 0.0000507 AC: 74AN: 1459474Hom.: 0 Cov.: 30 AF XY: 0.0000496 AC XY: 36AN XY: 726176
GnomAD4 genome AF: 0.0000395 AC: 6AN: 152046Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74288
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Dec 17, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 28, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 16, 2021 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 17, 2021 | The c.2512G>A (p.G838R) alteration is located in exon 18 (coding exon 18) of the LAMA2 gene. This alteration results from a G to A substitution at nucleotide position 2512, causing the glycine (G) at amino acid position 838 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
LAMA2-related muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 838 of the LAMA2 protein (p.Gly838Arg). This variant is present in population databases (rs150361703, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of LAMA2-related conditions (PMID: 36703223). ClinVar contains an entry for this variant (Variation ID: 573318). 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) performed at Invitae indicates that this missense variant is not expected to disrupt LAMA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 03, 2021 | - - |
Intellectual disability Benign:1
Likely benign, no assertion criteria provided | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Jan 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at