6-129280072-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM5BP4_StrongBP6BS2

The NM_000426.4(LAMA2):c.2462C>T(p.Thr821Met) variant causes a missense change. The variant allele was found at a frequency of 0.0023 in 1,612,224 control chromosomes in the GnomAD database, including 10 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. T821P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 10 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:6

Conservation

PhyloP100: 3.64

Publications

18 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-129280071-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 242608.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.055688918).

BP6

Variant 6-129280072-C-T is Benign according to our data. Variant chr6-129280072-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 162584.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

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.2462C>T	p.Thr821Met	missense	Exon 18 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.2462C>T	p.Thr821Met	missense	Exon 18 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.2462C>T	p.Thr821Met	missense	Exon 18 of 65	ENSP00000400365.2	P24043
LAMA2	ENST00000618192.5	TSL:5	c.2462C>T	p.Thr821Met	missense	Exon 18 of 66	ENSP00000480802.2	A0A087WX80
LAMA2	ENST00000617695.5	TSL:5	c.2462C>T	p.Thr821Met	missense	Exon 18 of 64	ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

256

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00358

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00260

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00193

AC:

485

AN:

251274

AF XY:

0.00183

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000639

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.000598

Gnomad FIN exome

AF:

0.00370

Gnomad NFE exome

AF:

0.00274

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00237

AC:

3457

AN:

1459934

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

1676

AN XY:

726406

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33416

American (AMR)

AF:

0.000807

AC:

AN:

44610

Ashkenazi Jewish (ASJ)

AF:

0.000843

AC:

AN:

26112

East Asian (EAS)

AF:

0.00121

AC:

AN:

39686

South Asian (SAS)

AF:

0.00116

AC:

100

AN:

86242

European-Finnish (FIN)

AF:

0.00341

AC:

182

AN:

53410

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00265

AC:

2939

AN:

1110382

Other (OTH)

AF:

0.00181

AC:

109

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

176

352

527

703

879

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<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:

0.00167

AC:

255

AN:

152290

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

118

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41570

American (AMR)

AF:

0.000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.00104

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00358

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00260

AC:

177

AN:

68018

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.00234

Hom.:

Bravo

AF:

0.00129

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00203

AC:

246

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00262

EpiControl

AF:

0.00261

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 (2)

not specified (2)

Congenital muscular dystrophy due to partial LAMA2 deficiency (1)

Intellectual disability (1)

LAMA2-related muscular dystrophy (1)

Merosin deficient congenital muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.062

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.056

MetaSVM

Uncertain

-0.061

MutationAssessor

Pathogenic

3.8

PhyloP100

3.6

PrimateAI

Benign

0.30

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

Polyphen

1.0

Vest4

0.56

MVP

0.85

MPC

0.47

ClinPred

0.080

GERP RS

4.0

Varity_R

0.76

gMVP

0.40

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over