rs3749877

Positions:

• chr6-129401244-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.5466A>G​(p.Glu1822=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 1,580,252 control chromosomes in the GnomAD database, including 181,718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20116 hom., cov: 32)
  • Exomes 𝑓: 0.47 (161602 hom.)
• Consequence: LAMA2 NM_000426.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.00

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=-0.49).
• BP6: Variant 6-129401244-A-G is Benign according to our data. Variant chr6-129401244-A-G is described in ClinVar as [Benign]. Clinvar id is 92966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129401244-A-G is described in Lovd as [Benign]. Variant chr6-129401244-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.613 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.5466A>G	p.Glu1822=	synonymous_variant	38/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.5466A>G	p.Glu1822=	synonymous_variant	38/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.5466A>G	p.Glu1822=	synonymous_variant	38/65	5	NM_000426.4
LAMA2	ENST00000618192.5	c.5730A>G	p.Glu1910=	synonymous_variant	39/66	5		P1
LAMA2	ENST00000617695.5	c.5466A>G	p.Glu1822=	synonymous_variant	38/64	5

Frequencies

GnomAD3 genomes AF: 0.508 AC: 77162 AN: 151922 Hom.: 20073 Cov.: 32

Gnomad AFR AF: 0.618

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.522

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.498

GnomAD3 exomes AF: 0.494 AC: 124058 AN: 251072 Hom.: 31198 AF XY: 0.493 AC XY: 66913 AN XY: 135694

Gnomad AFR exome AF: 0.622

Gnomad AMR exome AF: 0.473

Gnomad ASJ exome AF: 0.540

Gnomad EAS exome AF: 0.573

Gnomad SAS exome AF: 0.540

Gnomad FIN exome AF: 0.457

Gnomad NFE exome AF: 0.461

Gnomad OTH exome AF: 0.481

GnomAD4 exome AF: 0.469 AC: 670335 AN: 1428212 Hom.: 161602 Cov.: 32 AF XY: 0.471 AC XY: 335371 AN XY: 712156

Gnomad4 AFR exome AF: 0.632

Gnomad4 AMR exome AF: 0.476

Gnomad4 ASJ exome AF: 0.540

Gnomad4 EAS exome AF: 0.539

Gnomad4 SAS exome AF: 0.542

Gnomad4 FIN exome AF: 0.466

Gnomad4 NFE exome AF: 0.454

Gnomad4 OTH exome AF: 0.480

GnomAD4 genome AF: 0.508 AC: 77275 AN: 152040 Hom.: 20116 Cov.: 32 AF XY: 0.509 AC XY: 37828 AN XY: 74318

Gnomad4 AFR AF: 0.619

Gnomad4 AMR AF: 0.463

Gnomad4 ASJ AF: 0.522

Gnomad4 EAS AF: 0.553

Gnomad4 SAS AF: 0.535

Gnomad4 FIN AF: 0.450

Gnomad4 NFE AF: 0.455

Gnomad4 OTH AF: 0.496

Alfa AF: 0.469 Hom.: 19585

Bravo AF: 0.514

Asia WGS AF: 0.514 AC: 1788 AN: 3478

EpiCase AF: 0.461

EpiControl AF: 0.464

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	Eurofins Ntd Llc (ga)	Jul 18, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Merosin deficient congenital muscular dystrophy Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
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	- -

LAMA2-related muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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 12, 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	-0.49
CADD	Benign	5.4
DANN	Benign	0.71

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: rs3749877; hg19: chr6-129722389; COSMIC: COSV70340950;