chr6-129402359-G-T

Position:

• chr6-129402359-G-T

Variant summary

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

The NM_000426.4(LAMA2):​c.5598G>T​(p.Met1866Ile) 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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.42

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 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=0.1791707).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.5598G>T	p.Met1866Ile	missense_variant	39/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.5598G>T	p.Met1866Ile	missense_variant	39/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.5598G>T	p.Met1866Ile	missense_variant	39/65	5	NM_000426.4	ENSP00000400365
LAMA2	ENST00000618192.5	c.5862G>T	p.Met1954Ile	missense_variant	40/66	5		ENSP00000480802	P1
LAMA2	ENST00000617695.5	c.5598G>T	p.Met1866Ile	missense_variant	39/64	5		ENSP00000481744

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 07, 2017

The M1866I variant in the LAMA2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The M1866I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). However, the M1866I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret M1866I as a variant of uncertain significance. -

Merosin deficient congenital muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing;provider interpretation

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Jun 30, 2017

This 5 year old female has a history of global developmental delay, hypotonia, plagiocephaly, and abnormalities of blood clotting, and is compound heterozygous for variants in the LAMA2 gene. Compound heterozygous or homozygous LAMA2 variants are associated with a spectrum of muscular dystrophy phenotypes from severe, early-onset congenital muscular dystrophy to a milder later childhood onset limb-girdle muscular dystrophy. The c.5598G>T variant is absent from population databases (ExAC and gnomAD). Computational models are inconsistent. Follow-up testing showed mildly elevated CK levels 212 (reference range 26-192). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Uncertain	0.97
DEOGEN2	Benign	0.025	.;T;T
Eigen	Benign	-0.016
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	.;.;M
MutationTaster	Benign	0.52	D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	.;.;N
REVEL	Benign	0.053
Sift	Benign	0.13	.;.;T
Polyphen		0.13	.;.;B
Vest4		0.28
MutPred		0.45		Loss of ubiquitination at K1862 (P = 0.0394);Loss of ubiquitination at K1862 (P = 0.0394);Loss of ubiquitination at K1862 (P = 0.0394);
MVP		0.41
MPC		0.099
ClinPred		0.53	D
GERP RS		4.8
Varity_R		0.18
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs1554289926; hg19: chr6-129723504;