rs1554301854

Positions:

• chr6-129465139-TAATAGAG-TT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000426.4(LAMA2):​c.7156-5_7157delAATAGAGinsT​(p.Arg2386fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R2386?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LAMA2 NM_000426.4 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.36

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]

ENSG00000226149 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 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 6-129465140-AATAGAG-T is Pathogenic according to our data. Variant chr6-129465140-AATAGAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 477503.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.7156-5_7157delAATAGAGinsT	p.Arg2386fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	51/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.7156-5_7157delAATAGAGinsT	p.Arg2386fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	51/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.7156-5_7157delAATAGAGinsT	p.Arg2386fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	51/65	5	NM_000426.4	ENSP00000400365.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

LAMA2-related muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 03, 2016

For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency). While this particular variant has not been reported in the literature, truncating variants in LAMA2 are known to be pathogenic (PMID: 18700894). This variant, c.7156-5_7157delAATAGAGinsT, is a complex sequence change at the junction of intron 50 and exon 51 of the LAMA2 gene. The terminal 5 nucleotides of intron 50 and the first 2 nucleotides of exon 51 are deleted and replaced by a single T nucleotide.  This sequence change affects an acceptor splice site in intron 50 of the LAMA2 gene. It is expected to disrupt mRNA splicing or cause a frameshift and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554301854; hg19: chr6-129786285;