rs192317605

Positions:

• chr6-129267114-G-A
• chr6-129267114-G-C
• chr6-129267114-G-T

Variant summary

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

The NM_000426.4(LAMA2):​c.2217G>A​(p.Trp739Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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, single submitter P:2
• Conservation: PhyloP100: 2.34

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 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 6-129267114-G-A is Pathogenic according to our data. Variant chr6-129267114-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 988020.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.2217G>A	p.Trp739Ter	stop_gained	16/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.2217G>A	p.Trp739Ter	stop_gained	16/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.2217G>A	p.Trp739Ter	stop_gained	16/65	5	NM_000426.4	ENSP00000400365
LAMA2	ENST00000618192.5	c.2217G>A	p.Trp739Ter	stop_gained	16/66	5		ENSP00000480802	P1
LAMA2	ENST00000617695.5	c.2217G>A	p.Trp739Ter	stop_gained	16/64	5		ENSP00000481744

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Merosin deficient congenital muscular dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Medical Genetics, National Institute of Health

Nov 22, 2020

The variant was identified at homozygous state by Targeted next-generation sequencing of muscular dystrophies gene panel. It was confirmed by Sanger sequencing. Both parents present the variant at heterozygous state. This variant has never been reported in public human databases (accessed, Nov 2020) It was also not found in an in-house database of 100 Moroccan exomes (personal data). This variant is in agreement with the clinical data of a patient who presents a severe phenotype of MDC1A. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Apr 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.85	D
MutationTaster	Benign	1.0	A
Vest4		0.87
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs192317605; hg19: chr6-129588259; COSMIC: COSV70353022;