rs149347601

Positions:

chr6-129098187-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_000426.4(LAMA2):c.411G>A(p.Ala137Ala) 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -6.56

Variant links:

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]

LAMA2 links:

LAMA2 (HGNC:):

LAMA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Likely_benign=3, Uncertain_significance=1, 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 GnomAdExome4 at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4 linkuse as main transcript	c.411G>A	p.Ala137Ala	synonymous_variant	4/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 linkuse as main transcript	c.411G>A	p.Ala137Ala	synonymous_variant	4/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3 linkuse as main transcript	c.411G>A	p.Ala137Ala	synonymous_variant	4/65	5	NM_000426.4	ENSP00000400365.2		P24043

Frequencies

GnomAD3 genomes

AF:

0.00224

AC:

341

AN:

152080

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00310

AC XY:

421

AN XY:

135904

show subpopulations

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.:

Cov.:

AF XY:

0.00356

AC XY:

2586

AN XY:

727218

show subpopulations

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.:

Cov.:

AF XY:

0.00204

AC XY:

152

AN XY:

74424

show subpopulations

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.:

Bravo

AF:

0.00225

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00256

EpiControl

AF:

0.00445

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

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

not specified

Benign:2

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

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

Labcorp Genetics (formerly Invitae), Labcorp

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over