rs373997222
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000426.4(LAMA2):c.4993G>A(p.Gly1665Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000335 in 1,613,824 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). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. G1665G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000426.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA2 | NM_000426.4 | c.4993G>A | p.Gly1665Arg | missense_variant | 35/65 | ENST00000421865.3 | |
LAMA2 | NM_001079823.2 | c.4993G>A | p.Gly1665Arg | missense_variant | 35/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA2 | ENST00000421865.3 | c.4993G>A | p.Gly1665Arg | missense_variant | 35/65 | 5 | NM_000426.4 | ||
LAMA2 | ENST00000618192.5 | c.5257G>A | p.Gly1753Arg | missense_variant | 36/66 | 5 | P1 | ||
LAMA2 | ENST00000617695.5 | c.4993G>A | p.Gly1665Arg | missense_variant | 35/64 | 5 | |||
LAMA2 | ENST00000687590.1 | n.1413G>A | non_coding_transcript_exon_variant | 3/5 |
Frequencies
GnomAD3 genomes ? AF: 0.000191 AC: 29AN: 152182Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000459 AC: 115AN: 250414Hom.: 0 AF XY: 0.000495 AC XY: 67AN XY: 135296
GnomAD4 exome AF: 0.000350 AC: 512AN: 1461524Hom.: 0 Cov.: 31 AF XY: 0.000404 AC XY: 294AN XY: 727058
GnomAD4 genome ? AF: 0.000190 AC: 29AN: 152300Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16AN XY: 74460
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 17, 2023 | BP4 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 02, 2019 | See Variant Classification Assertion Criteria. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 16, 2023 | Variant summary: LAMA2 c.4993G>A (p.Gly1665Arg) results in a non-conservative amino acid change located in the laminin alpha, domain I (IPR009254) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 250414 control chromosomes, predominantly at a frequency of 0.0026 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in LAMA2 causing Laminin Alpha 2-Related Dystrophy phenotype (0.0022), suggesting that the variant may be a benign polymorphism found primarily in populations of East Asian origin. c.4993G>A has been reported in the literature in an individual suspected of Laminin Alpha 2-Related Dystrophy (Patel_2021). This report does not provide unequivocal conclusions about association of the variant with Laminin Alpha 2-Related Dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34925456). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Two submitters classified the variant as likely benign and one as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Congenital muscular dystrophy due to partial LAMA2 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at