rs2306942

Positions:

chr6-129314655-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000426.4(LAMA2):c.3412G>A(p.Val1138Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0581 in 1,612,986 control chromosomes in the GnomAD database, including 3,884 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.091 ( 933 hom., cov: 32)

Exomes 𝑓: 0.055 ( 2951 hom. )

Consequence

LAMA2
NM_000426.4 missense, splice_region

Scores

Splicing: ADA: 0.08566

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.15

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024026632).

BP6

Variant 6-129314655-G-A is Benign according to our data. Variant chr6-129314655-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129314655-G-A is described in Lovd as [Benign]. Variant chr6-129314655-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4 linkuse as main transcript	c.3412G>A	p.Val1138Met	missense_variant, splice_region_variant	24/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 linkuse as main transcript	c.3412G>A	p.Val1138Met	missense_variant, splice_region_variant	24/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
LAMA2	ENST00000421865.3 linkuse as main transcript	c.3412G>A	p.Val1138Met	missense_variant, splice_region_variant	24/65	5	NM_000426.4	ENSP00000400365
LAMA2	ENST00000618192.5 linkuse as main transcript	c.3676G>A	p.Val1226Met	missense_variant, splice_region_variant	25/66	5		ENSP00000480802	P1
LAMA2	ENST00000617695.5 linkuse as main transcript	c.3412G>A	p.Val1138Met	missense_variant, splice_region_variant	24/64	5		ENSP00000481744

Frequencies

GnomAD3 genomes

AF:

0.0905

AC:

13757

AN:

151978

Hom.:

929

Cov.:

show subpopulations

Gnomad AFR

AF:

0.188

Gnomad AMI

AF:

0.140

Gnomad AMR

AF:

0.0627

Gnomad ASJ

AF:

0.0519

Gnomad EAS

AF:

0.138

Gnomad SAS

AF:

0.103

Gnomad FIN

AF:

0.0293

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0439

Gnomad OTH

AF:

0.0872

GnomAD3 exomes

AF:

0.0651

AC:

16343

AN:

251076

Hom.:

816

AF XY:

0.0638

AC XY:

8664

AN XY:

135716

show subpopulations

Gnomad AFR exome

AF:

0.191

Gnomad AMR exome

AF:

0.0485

Gnomad ASJ exome

AF:

0.0515

Gnomad EAS exome

AF:

0.147

Gnomad SAS exome

AF:

0.0821

Gnomad FIN exome

AF:

0.0299

Gnomad NFE exome

AF:

0.0425

Gnomad OTH exome

AF:

0.0608

GnomAD4 exome

AF:

0.0547

AC:

79906

AN:

1460890

Hom.:

2951

Cov.:

AF XY:

0.0552

AC XY:

40139

AN XY:

726772

show subpopulations

Gnomad4 AFR exome

AF:

0.191

Gnomad4 AMR exome

AF:

0.0479

Gnomad4 ASJ exome

AF:

0.0521

Gnomad4 EAS exome

AF:

0.150

Gnomad4 SAS exome

AF:

0.0836

Gnomad4 FIN exome

AF:

0.0273

Gnomad4 NFE exome

AF:

0.0460

Gnomad4 OTH exome

AF:

0.0636

GnomAD4 genome

AF:

0.0907

AC:

13794

AN:

152096

Hom.:

933

Cov.:

AF XY:

0.0898

AC XY:

6680

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.189

Gnomad4 AMR

AF:

0.0626

Gnomad4 ASJ

AF:

0.0519

Gnomad4 EAS

AF:

0.138

Gnomad4 SAS

AF:

0.103

Gnomad4 FIN

AF:

0.0293

Gnomad4 NFE

AF:

0.0439

Gnomad4 OTH

AF:

0.0863

Alfa

AF:

0.0543

Hom.:

875

Bravo

AF:

0.0970

TwinsUK

AF:

0.0450

AC:

167

ALSPAC

AF:

0.0418

AC:

161

ESP6500AA

AF:

0.177

AC:

782

ESP6500EA

AF:

0.0469

AC:

403

ExAC

AF:

0.0680

AC:

8254

Asia WGS

AF:

0.0970

AC:

337

AN:

3478

EpiCase

AF:

0.0462

EpiControl

AF:

0.0466

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 10, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 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	Eurofins Ntd Llc (ga)	Jan 20, 2016	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Merosin deficient congenital muscular dystrophy

Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

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

Mar 06, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.015

.;T;T

Eigen

Benign

-0.030

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.87

D;D;D

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

.;.;L

MutationTaster

Benign

0.0019

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.43

.;.;N

REVEL

Benign

0.085

Sift

Benign

0.070

.;.;T

Polyphen

0.018

.;.;B

Vest4

0.18

MPC

0.11

ClinPred

0.011

GERP RS

4.7

Varity_R

0.059

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.086

dbscSNV1_RF

Benign

0.29

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