NM_000426.4:c.1798G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_000426.4(LAMA2):c.1798G>A(p.Gly600Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0177 in 1,601,344 control chromosomes in the GnomAD database, including 329 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 29 hom., cov: 32)

Exomes 𝑓: 0.018 ( 300 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.08

Publications

11 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 -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, PROVEAN [when BayesDel_addAF, BayesDel_noAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.008395851).

BP6

Variant 6-129250127-G-A is Benign according to our data. Variant chr6-129250127-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0129 (1958/152228) while in subpopulation SAS AF = 0.02 (96/4810). AF 95% confidence interval is 0.0184. There are 29 homozygotes in GnomAd4. There are 929 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4 link	c.1798G>A	p.Gly600Arg	missense_variant	Exon 13 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 link	c.1798G>A	p.Gly600Arg	missense_variant	Exon 13 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAMA2	ENST00000421865.3 link	c.1798G>A	p.Gly600Arg	missense_variant	Exon 13 of 65	5	NM_000426.4	ENSP00000400365.2	P24043
LAMA2	ENST00000618192.5 link	c.1798G>A	p.Gly600Arg	missense_variant	Exon 13 of 66	5		ENSP00000480802.2	A0A087WX80
LAMA2	ENST00000617695.5 link	c.1798G>A	p.Gly600Arg	missense_variant	Exon 13 of 64	5		ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1956

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00304

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0118

Gnomad ASJ

AF:

0.0233

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0195

Gnomad FIN

AF:

0.00998

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0193

Gnomad OTH

AF:

0.0167

GnomAD2 exomes

AF:

0.0139

AC:

3479

AN:

251146

AF XY:

0.0144

show subpopulations

Gnomad AFR exome

AF:

0.00363

Gnomad AMR exome

AF:

0.00847

Gnomad ASJ exome

AF:

0.0281

Gnomad EAS exome

AF:

0.000708

Gnomad FIN exome

AF:

0.00873

Gnomad NFE exome

AF:

0.0181

Gnomad OTH exome

AF:

0.0147

GnomAD4 exome

AF:

0.0182

AC:

26388

AN:

1449116

Hom.:

300

Cov.:

AF XY:

0.0184

AC XY:

13286

AN XY:

721918

show subpopulations

African (AFR)

AF:

0.00338

AC:

112

AN:

33100

American (AMR)

AF:

0.00879

AC:

393

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0254

AC:

661

AN:

26064

East Asian (EAS)

AF:

0.000682

AC:

AN:

39618

South Asian (SAS)

AF:

0.0158

AC:

1359

AN:

85994

European-Finnish (FIN)

AF:

0.00825

AC:

439

AN:

53238

Middle Eastern (MID)

AF:

0.0206

AC:

118

AN:

5734

European-Non Finnish (NFE)

AF:

0.0202

AC:

22280

AN:

1100734

Other (OTH)

AF:

0.0167

AC:

999

AN:

59930

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

1162

2324

3485

4647

5809

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

858

1716

2574

3432

4290

<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:

0.0129

AC:

1958

AN:

152228

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

929

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.00303

AC:

126

AN:

41536

American (AMR)

AF:

0.0118

AC:

180

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0233

AC:

AN:

3470

East Asian (EAS)

AF:

0.000579

AC:

AN:

5184

South Asian (SAS)

AF:

0.0200

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00998

AC:

106

AN:

10616

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0193

AC:

1310

AN:

68020

Other (OTH)

AF:

0.0166

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

106

212

319

425

531

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0169

Hom.:

Bravo

AF:

0.0124

TwinsUK

AF:

0.0165

AC:

ALSPAC

AF:

0.0187

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0206

AC:

177

ExAC

AF:

0.0132

AC:

1604

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.0212

EpiControl

AF:

0.0187

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Feb 08, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 18, 2022

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

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

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LAMA2: BS1, BS2 -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.071

.;T;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

D;D;D

MetaRNN

Benign

0.0084

T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Pathogenic

3.1

.;.;M

PhyloP100

6.1

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-6.6

.;.;D

REVEL

Uncertain

0.39

Sift

Benign

0.031

.;.;D

Polyphen

1.0

.;.;D

Vest4

0.68

MutPred

0.93

Loss of catalytic residue at P596 (P = 0.0966);Loss of catalytic residue at P596 (P = 0.0966);Loss of catalytic residue at P596 (P = 0.0966);

MPC

0.51

ClinPred

0.029

GERP RS

5.7

Varity_R

0.89

gMVP

0.89

Mutation Taster

=62/38

polymorphism

(source)

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

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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