6-129349348-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000426.4(LAMA2):c.4487C>T(p.Ala1496Val) variant causes a missense change. The variant allele was found at a frequency of 0.00368 in 1,613,554 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1496D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0033 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 31 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:12O:1

Conservation

PhyloP100: 4.30

Publications

12 publications found

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 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)

LAMA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.032247603).

BP6

Variant 6-129349348-C-T is Benign according to our data. Variant chr6-129349348-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196660.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00335 (510/152248) while in subpopulation AMR AF = 0.00504 (77/15276). AF 95% confidence interval is 0.00413. There are 1 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4 link	c.4487C>T	p.Ala1496Val	missense_variant	Exon 31 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 link	c.4487C>T	p.Ala1496Val	missense_variant	Exon 31 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3 link	c.4487C>T	p.Ala1496Val	missense_variant	Exon 31 of 65	5	NM_000426.4	ENSP00000400365.2		P24043

Frequencies

GnomAD3 genomes

AF:

0.00335

AC:

509

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00505

Gnomad ASJ

AF:

0.0253

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00390

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00373

AC:

937

AN:

251380

AF XY:

0.00384

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00260

Gnomad ASJ exome

AF:

0.0221

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00402

Gnomad NFE exome

AF:

0.00429

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00371

AC:

5424

AN:

1461306

Hom.:

Cov.:

AF XY:

0.00364

AC XY:

2649

AN XY:

726982

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33452

American (AMR)

AF:

0.00297

AC:

133

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0238

AC:

622

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.000325

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00328

AC:

175

AN:

53400

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00374

AC:

4157

AN:

1111578

Other (OTH)

AF:

0.00446

AC:

269

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

259

519

778

1038

1297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

158

316

474

632

790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00335

AC:

510

AN:

152248

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

231

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.000650

AC:

AN:

41548

American (AMR)

AF:

0.00504

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0253

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00273

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00391

AC:

266

AN:

68018

Other (OTH)

AF:

0.00664

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00377

Hom.:

Bravo

AF:

0.00342

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00442

AC:

ExAC

AF:

0.00334

AC:

406

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00507

EpiControl

AF:

0.00605

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:12Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Jun 09, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 03, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24957499, 28133863, 27854218) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LAMA2: BS2 -

Dec 15, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:2Benign:2

Dec 01, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2015

Center for Genetic Medicine Research, Children's National Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 29, 2025

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LAMA2 c.4487C>T (p.Ala1496Val) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0037 in 251380 control chromosomes, predominantly at a frequency of 0.0043 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 - fold of the estimated maximal expected allele frequency for a pathogenic variant in LAMA2 causing Laminin Alpha 2-Related Dystrophy phenotype (0.0022). To our knowledge, no occurrence of c.4487C>T in individuals affected with Laminin Alpha 2-Related Dystrophy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 196660). Based on the evidence outlined above, the variant was classified as likely benign. -

Merosin deficient congenital muscular dystrophy

Uncertain:1Benign:1Other:1

Aug 22, 2023

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Muscular dystrophy, limb-girdle, autosomal recessive 23

Pathogenic:1Benign:1

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

European Non-Finnish population allele frequency is 0.3978%% (rs147077184, 937/251380 alleles, 5 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -

Oct 05, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Congenital muscular dystrophy due to partial LAMA2 deficiency

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

LAMA2-related muscular dystrophy

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23

Benign:1

Feb 03, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

LAMA2-related disorder

Benign:1

Dec 31, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.034

.;T;T

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.032

T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.9

.;.;L

PhyloP100

4.3

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.3

.;.;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0080

.;.;D

Polyphen

0.99

.;.;D

Vest4

0.68

MVP

0.75

MPC

0.37

ClinPred

0.015

GERP RS

5.1

Varity_R

0.36

gMVP

0.47

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over