rs774051471
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000426.4(LAMA2):c.4692_4695dup(p.Arg1566CysfsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000274 in 1,461,806 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
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
LAMA2
NM_000426.4 frameshift
NM_000426.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.58
Genes affected
LAMA2 (HGNC:6482): (laminin subunit alpha 2) Laminin, an extracellular protein, is a major component of the basement membrane. It is thought to mediate the attachment, migration, and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components. It is composed of three subunits, alpha, beta, and gamma, which are bound to each other by disulfide bonds into a cross-shaped molecule. This gene encodes the alpha 2 chain, which constitutes one of the subunits of laminin 2 (merosin) and laminin 4 (s-merosin). Mutations in this gene have been identified as the cause of congenital merosin-deficient muscular dystrophy. Two transcript variants encoding different proteins have been found for this gene. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-129353328-G-GGCAT is Pathogenic according to our data. Variant chr6-129353328-G-GGCAT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA2 | NM_000426.4 | c.4692_4695dup | p.Arg1566CysfsTer13 | frameshift_variant | 32/65 | ENST00000421865.3 | |
LAMA2 | NM_001079823.2 | c.4692_4695dup | p.Arg1566CysfsTer13 | frameshift_variant | 32/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA2 | ENST00000421865.3 | c.4692_4695dup | p.Arg1566CysfsTer13 | frameshift_variant | 32/65 | 5 | NM_000426.4 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251424Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135892
GnomAD3 exomes
AF:
AC:
1
AN:
251424
Hom.:
AF XY:
AC XY:
0
AN XY:
135892
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461806Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727220
GnomAD4 exome
AF:
AC:
4
AN:
1461806
Hom.:
Cov.:
32
AF XY:
AC XY:
2
AN XY:
727220
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Merosin deficient congenital muscular dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 14, 2018 | - - |
LAMA2-related muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 04, 2022 | This sequence change creates a premature translational stop signal (p.Arg1566Cysfs*13) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 557277). This variant is also known as 4695_4698dupTGCA. This premature translational stop signal has been observed in individuals with congenital muscular dystrophy (PMID: 16216942). This variant is present in population databases (rs774051471, gnomAD 0.0009%). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at