rs746492572

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000426.4(LAMA2):c.5284C>G(p.Arg1762Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1762W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.50

Publications

1 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22669154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4 link	c.5284C>G	p.Arg1762Gly	missense_variant	Exon 37 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 link	c.5284C>G	p.Arg1762Gly	missense_variant	Exon 37 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAMA2	ENST00000421865.3 link	c.5284C>G	p.Arg1762Gly	missense_variant	Exon 37 of 65	5	NM_000426.4	ENSP00000400365.2	P24043
LAMA2	ENST00000618192.5 link	c.5548C>G	p.Arg1850Gly	missense_variant	Exon 38 of 66	5		ENSP00000480802.2	A0A087WX80
LAMA2	ENST00000617695.5 link	c.5284C>G	p.Arg1762Gly	missense_variant	Exon 37 of 64	5		ENSP00000481744.2	A0A087WYF1
LAMA2	ENST00000687590.1 link	n.1704C>G		non_coding_transcript_exon_variant	Exon 5 of 5

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151838

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250530

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461732

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1111924

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00000659

AC:

AN:

151838

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74144

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41270

American (AMR)

AF:

0.00

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67990

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 24, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5284C>G (p.R1762G) alteration is located in exon 37 (coding exon 37) of the LAMA2 gene. This alteration results from a C to G substitution at nucleotide position 5284, causing the arginine (R) at amino acid position 1762 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

LAMA2-related muscular dystrophy

Uncertain:1

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine with glycine at codon 1762 of the LAMA2 protein (p.Arg1762Gly). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs746492572, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with LAMA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 447688). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.033

.;T;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.56

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.82

T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.3

.;.;M

PhyloP100

1.5

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.5

.;.;N

REVEL

Benign

0.11

Sift

Benign

0.12

.;.;T

Polyphen

0.55

.;.;P

Vest4

0.21

MutPred

0.66

Loss of MoRF binding (P = 0.0435);Loss of MoRF binding (P = 0.0435);Loss of MoRF binding (P = 0.0435);

MVP

0.49

MPC

0.13

ClinPred

0.73

GERP RS

2.5

Varity_R

0.11

gMVP

0.11

Mutation Taster

=94/6

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over