chr6-129250127-G-T

Position:

• chr6-129250127-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000426.4(LAMA2):​c.1798G>T​(p.Gly600*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LAMA2 NM_000426.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.08

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]

ACMG classification

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 6-129250127-G-T is Pathogenic according to our data. Variant chr6-129250127-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1454202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.1798G>T	p.Gly600*	stop_gained	13/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.1798G>T	p.Gly600*	stop_gained	13/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.1798G>T	p.Gly600*	stop_gained	13/65	5	NM_000426.4	ENSP00000400365.2
LAMA2	ENST00000618192.5	c.1798G>T	p.Gly600*	stop_gained	13/66	5		ENSP00000480802.2
LAMA2	ENST00000617695.5	c.1798G>T	p.Gly600*	stop_gained	13/64	5		ENSP00000481744.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LAMA2-related muscular dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Servicio de Genética Del Instituto Nacional de Salud Del Niño, Ministerio de Salud	Nov 18, 2024	The variant NM_000426.4:c.1798G>T (p.Gly600)* introduces a premature stop codon at codon 600, likely resulting in a truncated protein or nonsense-mediated decay (NMD). According to ACMG/AMP guidelines, this variant meets the criteria for PVS1, PM2, and PP5, supporting its classification as pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 30, 2021	This sequence change creates a premature translational stop signal (p.Gly600*) 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). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with LAMA2-related conditions. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	43
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.79
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-129571272;