rs149347601

chr6-129098187-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000426.4(LAMA2):c.411G>A(p.Ala137=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00338 in 1,614,008 control chromosomes in the GnomAD database, including 18 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 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (18 hom.)
• Consequence: LAMA2 NM_000426.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -6.56

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-129098187-G-A is Benign according to our data. Variant chr6-129098187-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 256069.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=3}. Variant chr6-129098187-G-A is described in Lovd as [Benign]. Variant chr6-129098187-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-6.56 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00223 (340/152198) while in subpopulation SAS AF= 0.00664 (32/4820). AF 95% confidence interval is 0.00483. There are 0 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.411G>A	p.Ala137=	synonymous_variant	4/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.411G>A	p.Ala137=	synonymous_variant	4/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.411G>A	p.Ala137=	synonymous_variant	4/65	5	NM_000426.4

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 341 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00684

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00293 AC: 737 AN: 251438 Hom.: 4 AF XY: 0.00310 AC XY: 421 AN XY: 135904

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00461

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00376

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00350 AC: 5115 AN: 1461810 Hom.: 18 Cov.: 32 AF XY: 0.00356 AC XY: 2586 AN XY: 727218

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.00455

Gnomad4 EAS exome AF: 0.000731

Gnomad4 SAS exome AF: 0.00481

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00378

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00223 AC: 340 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00204 AC XY: 152 AN XY: 74424

Gnomad4 AFR AF: 0.000795

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00664

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00338

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00307 Hom.: 0

Bravo AF: 0.00225

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00445

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 03, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2021	This variant is associated with the following publications: (PMID: 12552556, 30055037) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	LAMA2: BP4, BP7, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 28, 2016	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.089
Dann	Benign	0.85

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: rs149347601; hg19: chr6-129419332;