rs202247790
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000426.4(LAMA2):c.2049_2050delAG(p.Arg683SerfsTer21) variant causes a frameshift change. The variant allele was found at a frequency of 0.000145 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000426.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LAMA2 | ENST00000421865.3 | c.2049_2050delAG | p.Arg683SerfsTer21 | frameshift_variant | Exon 14 of 65 | 5 | NM_000426.4 | ENSP00000400365.2 | ||
LAMA2 | ENST00000618192.5 | c.2049_2050delAG | p.Arg683SerfsTer21 | frameshift_variant | Exon 14 of 66 | 5 | ENSP00000480802.2 | |||
LAMA2 | ENST00000617695.5 | c.2049_2050delAG | p.Arg683SerfsTer21 | frameshift_variant | Exon 14 of 64 | 5 | ENSP00000481744.2 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000119 AC: 30AN: 251274Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135790
GnomAD4 exome AF: 0.000151 AC: 220AN: 1461760Hom.: 0 AF XY: 0.000139 AC XY: 101AN XY: 727194
GnomAD4 genome AF: 0.0000920 AC: 14AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74354
ClinVar
Submissions by phenotype
Merosin deficient congenital muscular dystrophy Pathogenic:9Other:1
The variant c.2045_2046delAG (p.Arg683Serfs*21) in the LAMA2 gene is reported as pathogenic for merosin deficient congenital muscular dystrophy in ClinVar (Variation ID: 38340) and as effect unknown in the Whole Genome datasets LAMA2 LOVD database v.3.0 (genomic variant: #0000691061). This variant creates a shift in the reading frame which is predicted to result in a premature stop codon 21 amino acids downstream and is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is reported with an estimated allele frequency of 0.0001 in gnomAD exomes, 0.0001 in gnomAD genomes and 0.0002 in NHLI Exome Sequencing Project (ESP), with no homozygous individuals reported. This variant – also known in the literature as c.2049_2050del or Lys682LysfsX22 – is one of the most frequently reported pathogenic variant in the LAMA2 gene, being identified in several individuals affected by congenital muscular dystrophy (e.g. PMIDs: 9541105, 27854218, 25544356, 30055037). -
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This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP2. -
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Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000116, PM2). The variant has been reported as pathogenic (ClinVar VCV000038340.19). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
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not provided Pathogenic:5
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PP4, PM2, PM3_strong, PS4_moderate, PVS1 -
Observed multiple times with a second pathogenic variant in unrelated individuals with merosin-deficient congenital muscular dystrophy (PMID: 9541105, 25544356, 24611677); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28133863, 28877744, 18700894, 25544356, 9541105, 27886618, 27854218, 28804634, 25663498, 31404137, 32827036, 33558818, 32528171, 37476021, 24611677, 11591858, 11369186, 28182637, 30055037, 30301903, 37206914, 36057830, 31066047, 34281576, 20207543, 36945402, 9674786, 37933889) -
LAMA2: PM3:Very Strong, PVS1, PM2 -
LAMA2-related muscular dystrophy Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg683Serfs*21) in the LAMA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMA2 are known to be pathogenic (PMID: 18700894, 32904964). This variant is present in population databases (rs751627052, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with congenital muscular dystrophy (PMID: 9541105, 18700894, 24611677, 25544356). For these reasons, this variant has been classified as Pathogenic. -
Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 Pathogenic:1
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Muscular dystrophy, limb-girdle, autosomal recessive 23 Pathogenic:1
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not specified Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at