rs1293303410
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000426.4(LAMA2):c.7658del(p.Ser2553TyrfsTer54) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,764 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S2553S) has been classified as Likely benign. 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA2 | NM_000426.4 | c.7658del | p.Ser2553TyrfsTer54 | frameshift_variant | 55/65 | ENST00000421865.3 | |
LOC124901401 | XR_007059767.1 | n.5035del | non_coding_transcript_exon_variant | 2/2 | |||
LAMA2 | NM_001079823.2 | c.7646del | p.Ser2549TyrfsTer54 | frameshift_variant | 54/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA2 | ENST00000421865.3 | c.7658del | p.Ser2553TyrfsTer54 | frameshift_variant | 55/65 | 5 | NM_000426.4 | ||
ENST00000442449.1 | n.63del | non_coding_transcript_exon_variant | 1/2 | 5 | |||||
ENST00000665046.1 | n.975+21257del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152110Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461654Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22AN XY: 727142
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74286
ClinVar
Submissions by phenotype
Merosin deficient congenital muscular dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 11, 2023 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Nov 05, 2017 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 10, 2022 | Reported in an individual with congenital muscular dystrophy who also harbored another variant (Mendell et al., 1998); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30055037, 10694916) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 17, 2021 | - - |
LAMA2-related muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 30, 2023 | This sequence change creates a premature translational stop signal (p.Ser2553Tyrfs*35) 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 (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with congenital muscular dystrophy (PMID: 10694916, 21520333, 30055037). This variant is also known as c.7707delC. ClinVar contains an entry for this variant (Variation ID: 477507). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at