rs1221715098
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000426.4(LAMA2):c.6992+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000103 in 1,459,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000426.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250460Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135356
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1459702Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 726256
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 29, 2018 | The c.6992+5G>A variant in the LAMA2 gene has been reported previously in the heterozygous state with a second LAMA2 variant in an individual with limb girdle muscular dystrophy, however, segregation studies to confirm phase were only performed on one parent (Harris et al., 2017). This variant is predicted to destroy the splice donor site in intron 49. Both in silico predictors and evolutionary conservation support a deleterious effect in this gene for which loss-of-function is a known mechanism for disease. The c.6992+5G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.6992+5G>A as a likely pathogenic variant. - |
Muscular dystrophy, limb-girdle, autosomal recessive 23 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Institute of Human Genetics, University of Wuerzburg | - | - - |
Merosin deficient congenital muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 01, 2018 | - - |
LAMA2-related muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 04, 2024 | This sequence change falls in intron 49 of the LAMA2 gene. It does not directly change the encoded amino acid sequence of the LAMA2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has been observed in individual(s) with limb girdle muscular dystrophy (PMID: 28877744). ClinVar contains an entry for this variant (Variation ID: 546142). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
LAMA2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 20, 2023 | The LAMA2 c.6992+5G>A variant is predicted to interfere with splicing. This variant has been reported in the heterozygous state (along with a second variant) in an individual with white matter changes (Table 1, individual 32, Harris et al. 2017. PubMed ID: 28877744). A skin biopsy for this individual demonstrated partial absence of laminin a2. In the gnomAD public population database this variant has been reported in one of ~250,000 alleles (https://gnomad.broadinstitute.org/variant/6-129781474-G-A), and is interpreted as uncertain significance and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/546142/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at