rs2244008

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000426.4(LAMA2):c.7906A>G(p.Thr2636Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0722 in 1,605,722 control chromosomes in the GnomAD database, including 4,812 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2636T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.087 ( 631 hom., cov: 32)

Exomes 𝑓: 0.071 ( 4181 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.99

Publications

30 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:

ENSG00000226149 (HGNC:):

ENSG00000226149 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020777285).

BP6

Variant 6-129491908-A-G is Benign according to our data. Variant chr6-129491908-A-G is described in ClinVar as Benign. ClinVar VariationId is 92989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4 link	c.7906A>G	p.Thr2636Ala	missense_variant	Exon 57 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 link	c.7894A>G	p.Thr2632Ala	missense_variant	Exon 56 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3 link	c.7906A>G	p.Thr2636Ala	missense_variant	Exon 57 of 65	5	NM_000426.4	ENSP00000400365.2

Frequencies

GnomAD3 genomes

AF:

0.0875

AC:

13305

AN:

152096

Hom.:

634

Cov.:

show subpopulations

Gnomad AFR

AF:

0.113

Gnomad AMI

AF:

0.0888

Gnomad AMR

AF:

0.0737

Gnomad ASJ

AF:

0.0833

Gnomad EAS

AF:

0.164

Gnomad SAS

AF:

0.114

Gnomad FIN

AF:

0.112

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0638

Gnomad OTH

AF:

0.0824

GnomAD2 exomes

AF:

0.0872

AC:

21834

AN:

250466

AF XY:

0.0862

show subpopulations

Gnomad AFR exome

AF:

0.112

Gnomad AMR exome

AF:

0.0733

Gnomad ASJ exome

AF:

0.0855

Gnomad EAS exome

AF:

0.182

Gnomad FIN exome

AF:

0.113

Gnomad NFE exome

AF:

0.0672

Gnomad OTH exome

AF:

0.0751

GnomAD4 exome

AF:

0.0706

AC:

102602

AN:

1453508

Hom.:

4181

Cov.:

AF XY:

0.0711

AC XY:

51460

AN XY:

723670

show subpopulations

African (AFR)

AF:

0.109

AC:

3622

AN:

33270

American (AMR)

AF:

0.0704

AC:

3146

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.0855

AC:

2230

AN:

26078

East Asian (EAS)

AF:

0.163

AC:

6433

AN:

39580

South Asian (SAS)

AF:

0.0890

AC:

7659

AN:

86066

European-Finnish (FIN)

AF:

0.114

AC:

6104

AN:

53396

Middle Eastern (MID)

AF:

0.0601

AC:

346

AN:

5756

European-Non Finnish (NFE)

AF:

0.0619

AC:

68356

AN:

1104540

Other (OTH)

AF:

0.0783

AC:

4706

AN:

60128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

4341

8682

13023

17364

21705

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2638

5276

7914

10552

13190

<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:

0.0874

AC:

13302

AN:

152214

Hom.:

631

Cov.:

AF XY:

0.0906

AC XY:

6745

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.113

AC:

4691

AN:

41542

American (AMR)

AF:

0.0737

AC:

1127

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0833

AC:

289

AN:

3470

East Asian (EAS)

AF:

0.164

AC:

848

AN:

5174

South Asian (SAS)

AF:

0.112

AC:

539

AN:

4814

European-Finnish (FIN)

AF:

0.112

AC:

1189

AN:

10598

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0638

AC:

4342

AN:

68006

Other (OTH)

AF:

0.0815

AC:

172

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

623

1246

1868

2491

3114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

296

444

592

740

<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:

0.0723

Hom.:

1461

Bravo

AF:

0.0867

TwinsUK

AF:

0.0647

AC:

240

ALSPAC

AF:

0.0602

AC:

232

ESP6500AA

AF:

0.116

AC:

509

ESP6500EA

AF:

0.0630

AC:

542

ExAC

AF:

0.0879

AC:

10668

Asia WGS

AF:

0.119

AC:

412

AN:

3478

EpiCase

AF:

0.0632

EpiControl

AF:

0.0636

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jan 28, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 20, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

- -

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

Jan 13, 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

0.075

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.033

.;T;T

Eigen

Benign

-0.0057

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.78

T;T;T

MetaRNN

Benign

0.0021

T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.3

.;.;L

PhyloP100

4.0

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.1

.;.;D

REVEL

Benign

0.27

Sift

Benign

0.035

.;.;D

Polyphen

0.015

.;.;B

Vest4

0.082

MPC

0.088

ClinPred

0.035

GERP RS

5.5

Varity_R

0.16

gMVP

0.45

Mutation Taster

=93/7

polymorphism (auto)

(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