rs374888837

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000426.4(LAMA2):c.8905C>T(p.Arg2969Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000669 in 1,613,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R2969H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.67

Publications

2 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Myriad Women’s Health
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: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.843

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000426.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	NM_000426.4	MANE Select	c.8905C>T	p.Arg2969Cys	missense	Exon 63 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.8893C>T	p.Arg2965Cys	missense	Exon 62 of 64	NP_001073291.2	A0A087WYF1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LAMA2	ENST00000421865.3	TSL:5 MANE Select	c.8905C>T	p.Arg2969Cys	missense	Exon 63 of 65	ENSP00000400365.2	P24043
LAMA2	ENST00000618192.5	TSL:5	c.9169C>T	p.Arg3057Cys	missense	Exon 64 of 66	ENSP00000480802.2	A0A087WX80
LAMA2	ENST00000617695.5	TSL:5	c.8893C>T	p.Arg2965Cys	missense	Exon 62 of 64	ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000876

AC:

AN:

251202

AF XY:

0.0000737

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.0000527

AC:

AN:

1461078

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

726900

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33458

American (AMR)

AF:

0.0000671

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26118

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39664

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

1111334

Other (OTH)

AF:

0.0000663

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000204

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.000482

AC:

AN:

41526

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67996

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

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:

0.000102

Hom.:

Bravo

AF:

0.000140

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000988

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital muscular dystrophy due to partial LAMA2 deficiency (1)

Inborn genetic diseases (1)

LAMA2-related muscular dystrophy (2)

Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 (1)

not provided (1)

Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.082

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.079

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

0.028

MutationAssessor

Pathogenic

3.3

PhyloP100

6.7

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-6.6

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

Polyphen

1.0

Vest4

0.89

MVP

0.88

MPC

0.56

ClinPred

0.88

GERP RS

4.9

Varity_R

0.90

gMVP

0.83

Mutation Taster

=58/42

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over