6-129492462-G-A

Position:

• chr6-129492462-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000426.4(LAMA2):​c.8223G>A​(p.Thr2741=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,612,948 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: LAMA2 NM_000426.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.294

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-129492462-G-A is Benign according to our data. Variant chr6-129492462-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 355301.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr6-129492462-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.294 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.8223G>A	p.Thr2741=	synonymous_variant	58/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.8211G>A	p.Thr2737=	synonymous_variant	57/64		NP_001073291.2
LOC102723409	XR_001743860.2			downstream_gene_variant
LOC102723409	XR_007059756.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.8223G>A	p.Thr2741=	synonymous_variant	58/65	5	NM_000426.4	ENSP00000400365
	ENST00000665046.1	n.975+10143C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 18 AN: 151720 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000287 AC: 72 AN: 250710 Hom.: 0 AF XY: 0.000265 AC XY: 36 AN XY: 135598

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.000134 AC: 196 AN: 1461110 Hom.: 1 Cov.: 32 AF XY: 0.000140 AC XY: 102 AN XY: 726904

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000765

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000119 AC: 18 AN: 151838 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74244

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000394

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000133

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000405 Hom.: 0

Bravo AF: 0.000242

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	LAMA2: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 26, 2015	- -

Congenital muscular dystrophy due to partial LAMA2 deficiency Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

LAMA2-related muscular dystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.22
DANN	Benign	0.50

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: rs150596964; hg19: chr6-129813607;