6-129291620-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000426.4(LAMA2):c.2756G>T(p.Arg919Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00852 in 1,613,110 control chromosomes in the GnomAD database, including 749 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R919G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.042 (378 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (371 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.178

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005194962).
• BP6: Variant 6-129291620-G-T is Benign according to our data. Variant chr6-129291620-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 92948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129291620-G-T is described in Lovd as [Benign]. Variant chr6-129291620-G-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.2756G>T	p.Arg919Leu	missense_variant	20/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.2756G>T	p.Arg919Leu	missense_variant	20/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.2756G>T	p.Arg919Leu	missense_variant	20/65	5	NM_000426.4
LAMA2	ENST00000618192.5	c.2756G>T	p.Arg919Leu	missense_variant	20/66	5		P1
LAMA2	ENST00000617695.5	c.2756G>T	p.Arg919Leu	missense_variant	20/64	5

Frequencies

GnomAD3 genomes AF: 0.0413 AC: 6287 AN: 152106 Hom.: 377 Cov.: 33

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.0392

GnomAD3 exomes AF: 0.0116 AC: 2909 AN: 251366 Hom.: 157 AF XY: 0.00882 AC XY: 1198 AN XY: 135856

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.00804

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00595

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000871

Gnomad OTH exome AF: 0.00879

GnomAD4 exome AF: 0.00508 AC: 7418 AN: 1460886 Hom.: 371 Cov.: 30 AF XY: 0.00469 AC XY: 3411 AN XY: 726832

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.00883

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00573

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000949

Gnomad4 OTH exome AF: 0.0114

GnomAD4 genome AF: 0.0415 AC: 6318 AN: 152224 Hom.: 378 Cov.: 33 AF XY: 0.0394 AC XY: 2931 AN XY: 74450

Gnomad4 AFR AF: 0.140

Gnomad4 AMR AF: 0.0172

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0110

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.0388

Alfa AF: 0.00704 Hom.: 101

Bravo AF: 0.0464

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.133 AC: 587

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.0141 AC: 1712

Asia WGS AF: 0.0180 AC: 61 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 18, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

LAMA2-related muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Congenital muscular dystrophy due to partial LAMA2 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	7.8
Dann	Uncertain	0.98
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.42	T;T;T
MetaRNN	Benign	0.0052	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.63	N
PrimateAI	Benign	0.21	T
Polyphen		0.0010	.;.;B
Vest4		0.20
MPC		0.11
ClinPred		0.013	T
GERP RS		-1.9
Varity_R		0.13
gMVP		0.23

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: rs35277491; hg19: chr6-129612765;