rs398123383
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000426.4(LAMA2):c.6955C>T(p.Arg2319Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000242 in 1,611,908 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R2319R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000426.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA2 | NM_000426.4 | c.6955C>T | p.Arg2319Ter | stop_gained | 49/65 | ENST00000421865.3 | |
LAMA2 | NM_001079823.2 | c.6955C>T | p.Arg2319Ter | stop_gained | 49/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA2 | ENST00000421865.3 | c.6955C>T | p.Arg2319Ter | stop_gained | 49/65 | 5 | NM_000426.4 | ||
ENST00000665046.1 | n.976-19035G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151800Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250586Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135416
GnomAD4 exome AF: 0.0000253 AC: 37AN: 1460108Hom.: 0 Cov.: 31 AF XY: 0.0000262 AC XY: 19AN XY: 726424
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151800Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74110
ClinVar
Submissions by phenotype
Merosin deficient congenital muscular dystrophy Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Stop-gained (nonsense) is 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. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000092980 / PMID: 9674786 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 16, 2023 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Apr 07, 2017 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 01, 2021 | Nonsense 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; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29465610, 25525159, 11369186, 32936536, 29376585, 9674786, 28445022, 30055037) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 30, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 23, 2016 | - - |
Myalgia;C0241005:Elevated circulating creatine kinase concentration;C1850830:Exercise-induced myalgia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
LAMA2-related muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 05, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 92980). This variant is also known as c.7004C>T. This premature translational stop signal has been observed in individuals with congenital muscular dystrophy (PMID: 9674786, 28445022, 30055037). This variant is present in population databases (rs398123383, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Arg2319*) 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at