rs3816665

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.1856G>A(p.Arg619His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,595,278 control chromosomes in the GnomAD database, including 27,206 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R619C) has been classified as Benign.

Frequency

Genomes: 𝑓 0.25 ( 7179 hom., cov: 32)

Exomes 𝑓: 0.15 ( 20027 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.57

Publications

28 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.9240298E-5).

BP6

Variant 6-129250185-G-A is Benign according to our data. Variant chr6-129250185-G-A is described in ClinVar as Benign. ClinVar VariationId is 92943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4 link	c.1856G>A	p.Arg619His	missense_variant	Exon 13 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 link	c.1856G>A	p.Arg619His	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.1856G>A	p.Arg619His	missense_variant	Exon 13 of 65	5	NM_000426.4	ENSP00000400365.2	P24043
LAMA2	ENST00000618192.5 link	c.1856G>A	p.Arg619His	missense_variant	Exon 13 of 66	5		ENSP00000480802.2	A0A087WX80
LAMA2	ENST00000617695.5 link	c.1856G>A	p.Arg619His	missense_variant	Exon 13 of 64	5		ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes

AF:

0.250

AC:

37925

AN:

151884

Hom.:

7155

Cov.:

show subpopulations

Gnomad AFR

AF:

0.533

Gnomad AMI

AF:

0.135

Gnomad AMR

AF:

0.135

Gnomad ASJ

AF:

0.153

Gnomad EAS

AF:

0.0903

Gnomad SAS

AF:

0.229

Gnomad FIN

AF:

0.192

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.134

Gnomad OTH

AF:

0.211

GnomAD2 exomes

AF:

0.174

AC:

43614

AN:

251036

AF XY:

0.172

show subpopulations

Gnomad AFR exome

AF:

0.542

Gnomad AMR exome

AF:

0.119

Gnomad ASJ exome

AF:

0.156

Gnomad EAS exome

AF:

0.0785

Gnomad FIN exome

AF:

0.190

Gnomad NFE exome

AF:

0.136

Gnomad OTH exome

AF:

0.162

GnomAD4 exome

AF:

0.151

AC:

217711

AN:

1443276

Hom.:

20027

Cov.:

AF XY:

0.153

AC XY:

109798

AN XY:

719284

show subpopulations

African (AFR)

AF:

0.547

AC:

17893

AN:

32732

American (AMR)

AF:

0.122

AC:

5468

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.157

AC:

4080

AN:

26034

East Asian (EAS)

AF:

0.0952

AC:

3769

AN:

39600

South Asian (SAS)

AF:

0.232

AC:

19901

AN:

85744

European-Finnish (FIN)

AF:

0.184

AC:

9749

AN:

53122

Middle Eastern (MID)

AF:

0.190

AC:

1086

AN:

5724

European-Non Finnish (NFE)

AF:

0.133

AC:

145811

AN:

1095870

Other (OTH)

AF:

0.167

AC:

9954

AN:

59740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

7896

15792

23689

31585

39481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5418

10836

16254

21672

27090

<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:

0.250

AC:

37996

AN:

152002

Hom.:

7179

Cov.:

AF XY:

0.249

AC XY:

18520

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.533

AC:

22072

AN:

41412

American (AMR)

AF:

0.134

AC:

2055

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.153

AC:

530

AN:

3468

East Asian (EAS)

AF:

0.0899

AC:

465

AN:

5172

South Asian (SAS)

AF:

0.228

AC:

1097

AN:

4816

European-Finnish (FIN)

AF:

0.192

AC:

2027

AN:

10552

Middle Eastern (MID)

AF:

0.177

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.134

AC:

9128

AN:

67970

Other (OTH)

AF:

0.211

AC:

447

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1217

2434

3650

4867

6084

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

366

732

1098

1464

1830

<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:

0.171

Hom.:

10721

Bravo

AF:

0.257

TwinsUK

AF:

0.136

AC:

506

ALSPAC

AF:

0.132

AC:

508

ESP6500AA

AF:

0.523

AC:

2304

ESP6500EA

AF:

0.140

AC:

1204

ExAC

AF:

0.183

AC:

22176

Asia WGS

AF:

0.200

AC:

697

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 05, 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. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: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

- -

Merosin deficient congenital muscular dystrophy

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 13, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

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

0.062

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.0070

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.015

.;T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.38

T;T;T

MetaRNN

Benign

0.000039

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

.;.;L

PhyloP100

-1.6

PrimateAI

Benign

0.22

PROVEAN

Benign

0.050

.;.;N

REVEL

Benign

0.063

Sift

Benign

0.29

.;.;T

Polyphen

0.0

.;.;B

Vest4

0.030

MPC

0.11

ClinPred

0.0018

GERP RS

-5.1

Varity_R

0.022

gMVP

0.34

Mutation Taster

=100/0

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