6-129291663-A-G

Position:

• chr6-129291663-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000426.4(LAMA2):​c.2799A>G​(p.Gln933=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,612,996 control chromosomes in the GnomAD database, including 52,290 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5756 hom., cov: 33)
  • Exomes 𝑓: 0.25 (46534 hom.)
• Consequence: LAMA2 NM_000426.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.04

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-129291663-A-G is Benign according to our data. Variant chr6-129291663-A-G is described in ClinVar as [Benign]. Clinvar id is 92949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129291663-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.2799A>G	p.Gln933=	synonymous_variant	20/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.2799A>G	p.Gln933=	synonymous_variant	20/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.2799A>G	p.Gln933=	synonymous_variant	20/65	5	NM_000426.4	ENSP00000400365
LAMA2	ENST00000618192.5	c.2799A>G	p.Gln933=	synonymous_variant	20/66	5		ENSP00000480802	P1
LAMA2	ENST00000617695.5	c.2799A>G	p.Gln933=	synonymous_variant	20/64	5		ENSP00000481744

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40759 AN: 152006 Hom.: 5749 Cov.: 33

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.261

GnomAD3 exomes AF: 0.270 AC: 67795 AN: 251332 Hom.: 9653 AF XY: 0.269 AC XY: 36477 AN XY: 135838

Gnomad AFR exome AF: 0.330

Gnomad AMR exome AF: 0.270

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.435

Gnomad SAS exome AF: 0.302

Gnomad FIN exome AF: 0.291

Gnomad NFE exome AF: 0.225

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.246 AC: 359857 AN: 1460872 Hom.: 46534 Cov.: 33 AF XY: 0.248 AC XY: 180095 AN XY: 726790

Gnomad4 AFR exome AF: 0.339

Gnomad4 AMR exome AF: 0.266

Gnomad4 ASJ exome AF: 0.238

Gnomad4 EAS exome AF: 0.484

Gnomad4 SAS exome AF: 0.298

Gnomad4 FIN exome AF: 0.284

Gnomad4 NFE exome AF: 0.228

Gnomad4 OTH exome AF: 0.262

GnomAD4 genome AF: 0.268 AC: 40787 AN: 152124 Hom.: 5756 Cov.: 33 AF XY: 0.271 AC XY: 20144 AN XY: 74360

Gnomad4 AFR AF: 0.327

Gnomad4 AMR AF: 0.234

Gnomad4 ASJ AF: 0.228

Gnomad4 EAS AF: 0.455

Gnomad4 SAS AF: 0.282

Gnomad4 FIN AF: 0.293

Gnomad4 NFE AF: 0.224

Gnomad4 OTH AF: 0.259

Alfa AF: 0.217 Hom.: 1962

Bravo AF: 0.270

Asia WGS AF: 0.344 AC: 1196 AN: 3478

EpiCase AF: 0.232

EpiControl AF: 0.230

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2012	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Merosin deficient congenital muscular dystrophy Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

LAMA2-related muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 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. -

Muscular dystrophy, limb-girdle, autosomal recessive 23 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.53
DANN	Benign	0.45

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: rs1027199; hg19: chr6-129612808; COSMIC: COSV70346677;