chr6-129492470-C-G

Position:

• chr6-129492470-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000426.4(LAMA2):​c.8231C>G​(p.Pro2744Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.60

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20409101).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.8231C>G	p.Pro2744Arg	missense_variant	58/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.8219C>G	p.Pro2740Arg	missense_variant	57/64		NP_001073291.2
LOC102723409	XR_001743860.2	n.*12G>C		downstream_gene_variant
LOC102723409	XR_007059756.1	n.*12G>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.8231C>G	p.Pro2744Arg	missense_variant	58/65	5	NM_000426.4	ENSP00000400365.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

LAMA2-related muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LAMA2 protein function. ClinVar contains an entry for this variant (Variation ID: 477515). This variant has not been reported in the literature in individuals affected with LAMA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2744 of the LAMA2 protein (p.Pro2744Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	.;T;T
Eigen	Benign	-0.081
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	.;.;M
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	.;.;N
REVEL	Benign	0.094
Sift	Benign	0.080	.;.;T
Polyphen		0.88	.;.;P
Vest4		0.29
MutPred		0.32		.;.;Gain of catalytic residue at P2744 (P = 0.0764);
MVP		0.60
MPC		0.35
ClinPred		0.57	D
GERP RS		5.4
Varity_R		0.070
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1554310317; hg19: chr6-129813615;