chr6-129328306-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000426.4(LAMA2):c.4205G>A(p.Arg1402His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. R1402C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.318

Publications

4 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025323749).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4 link	c.4205G>A	p.Arg1402His	missense_variant	Exon 29 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 link	c.4205G>A	p.Arg1402His	missense_variant	Exon 29 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAMA2	ENST00000421865.3 link	c.4205G>A	p.Arg1402His	missense_variant	Exon 29 of 65	5	NM_000426.4	ENSP00000400365.2	P24043
LAMA2	ENST00000618192.5 link	c.4469G>A	p.Arg1490His	missense_variant	Exon 30 of 66	5		ENSP00000480802.2	A0A087WX80
LAMA2	ENST00000617695.5 link	c.4205G>A	p.Arg1402His	missense_variant	Exon 29 of 64	5		ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000604

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000716

AC:

AN:

251334

AF XY:

0.0000810

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000127

AC:

185

AN:

1461844

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33480

American (AMR)

AF:

0.000157

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000139

AC:

155

AN:

1111990

Other (OTH)

AF:

0.0000662

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000236

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000602

AC:

AN:

41546

American (AMR)

AF:

0.000392

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000242

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 22, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4205G>A (p.R1402H) alteration is located in exon 29 (coding exon 29) of the LAMA2 gene. This alteration results from a G to A substitution at nucleotide position 4205, causing the arginine (R) at amino acid position 1402 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Mar 02, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital muscular dystrophy due to partial LAMA2 deficiency

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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

Uncertain:1

Oct 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

LAMA2-related muscular dystrophy

Benign:1

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.028

.;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.071

LIST_S2

Benign

0.70

T;T;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.025

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.3

.;.;L

PhyloP100

0.32

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.5

.;.;N

REVEL

Benign

0.068

Sift

Benign

0.089

.;.;T

Polyphen

0.010

.;.;B

Vest4

0.13

MVP

0.45

MPC

0.12

ClinPred

0.035

GERP RS

0.16

Varity_R

0.031

gMVP

0.27

Mutation Taster

=92/8

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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chr6-129328306-G-A

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