rs2306942

Variant names:

• chr6-129314655-G-A
• rs2306942
• NM_000426.4:c.3412G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-129314655-G-A
• chr6-129314655-G-C
• chr6-129314655-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 17/23 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V1138V) has been classified 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
• Publications: 31 publications found

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 Gene-Disease associations (from GenCC):

• congenital merosin-deficient muscular dystrophy 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
• LAMA2-related muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy, limb-girdle, autosomal recessive 23

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 92952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.3412G>A	p.Val1138Met	missense_variant, splice_region_variant	Exon 24 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.3412G>A	p.Val1138Met	missense_variant, splice_region_variant	Exon 24 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.3412G>A	p.Val1138Met	missense_variant, splice_region_variant	Exon 24 of 65	5	NM_000426.4	ENSP00000400365.2
LAMA2	ENST00000618192.5	c.3676G>A	p.Val1226Met	missense_variant, splice_region_variant	Exon 25 of 66	5		ENSP00000480802.2
LAMA2	ENST00000617695.5	c.3412G>A	p.Val1138Met	missense_variant, splice_region_variant	Exon 24 of 64	5		ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.0905 AC: 13757 AN: 151978 Hom.: 929 Cov.: 32

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

GnomAD2 exomes AF: 0.0651 AC: 16343 AN: 251076 AF XY: 0.0638

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 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.: 32 AF XY: 0.0552 AC XY: 40139 AN XY: 726772

African (AFR) AF: 0.191 AC: 6376 AN: 33460

American (AMR) AF: 0.0479 AC: 2143 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0521 AC: 1362 AN: 26122

East Asian (EAS) AF: 0.150 AC: 5968 AN: 39684

South Asian (SAS) AF: 0.0836 AC: 7207 AN: 86160

European-Finnish (FIN) AF: 0.0273 AC: 1457 AN: 53342

Middle Eastern (MID) AF: 0.0826 AC: 444 AN: 5376

European-Non Finnish (NFE) AF: 0.0460 AC: 51116 AN: 1111720

Other (OTH) AF: 0.0636 AC: 3833 AN: 60312

GnomAD4 genome AF: 0.0907 AC: 13794 AN: 152096 Hom.: 933 Cov.: 32 AF XY: 0.0898 AC XY: 6680 AN XY: 74376

African (AFR) AF: 0.189 AC: 7811 AN: 41430

American (AMR) AF: 0.0626 AC: 957 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0519 AC: 180 AN: 3468

East Asian (EAS) AF: 0.138 AC: 712 AN: 5162

South Asian (SAS) AF: 0.103 AC: 496 AN: 4814

European-Finnish (FIN) AF: 0.0293 AC: 311 AN: 10612

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0439 AC: 2985 AN: 68010

Other (OTH) AF: 0.0863 AC: 182 AN: 2108

Alfa AF: 0.0588 Hom.: 2062

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

Submissions by phenotype

not specified Benign:7

Jan 20, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 10, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Merosin deficient congenital muscular dystrophy Benign:1

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

LAMA2-related muscular dystrophy Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital muscular dystrophy due to partial LAMA2 deficiency Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	.;T;T
Eigen	Benign	-0.030
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D;D;D
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	.;.;L
PhyloP100		3.1
PrimateAI	Benign	0.39	T
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	T
GERP RS		4.7
Varity_R		0.059
gMVP		0.46
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2306942; hg19: chr6-129635800; COSMIC: COSV70347005;