6-129342380-G-C

Position:

• chr6-129342380-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000426.4(LAMA2):​c.4349G>C​(p.Arg1450Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1450Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05

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]

LAMA2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.4349G>C	p.Arg1450Pro	missense_variant	30/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.4349G>C	p.Arg1450Pro	missense_variant	30/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.4349G>C	p.Arg1450Pro	missense_variant	30/65	5	NM_000426.4	ENSP00000400365.2
LAMA2	ENST00000618192.5	c.4613G>C	p.Arg1538Pro	missense_variant	31/66	5		ENSP00000480802.2
LAMA2	ENST00000617695.5	c.4349G>C	p.Arg1450Pro	missense_variant	30/64	5		ENSP00000481744.2
LAMA2	ENST00000692206.1	n.-3G>C		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461030 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726860

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

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

Apr 05, 2019

This sequence change replaces arginine with proline at codon 1450 of the LAMA2 protein (p.Arg1450Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LAMA2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	.;T;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	-0.078	T
MutationAssessor	Pathogenic	3.5	.;.;H
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.4	.;.;N
REVEL	Uncertain	0.52
Sift	Benign	0.16	.;.;T
Polyphen		1.0	.;.;D
Vest4		0.72
MutPred		0.63		Gain of catalytic residue at D1446 (P = 0.105);Gain of catalytic residue at D1446 (P = 0.105);Gain of catalytic residue at D1446 (P = 0.105);
MVP		0.89
MPC		0.57
ClinPred		0.94	D
GERP RS		3.8
Varity_R		0.54
gMVP		0.81

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: rs148905630; hg19: chr6-129663525;