rs4404787

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000426.4(LAMA2):c.381C>A(p.Thr127Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.963 in 1,563,004 control chromosomes in the GnomAD database, including 725,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T127T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.95 ( 69134 hom., cov: 32)

Exomes 𝑓: 0.96 ( 656316 hom. )

Consequence

LAMA2
NM_000426.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -2.66

Publications

20 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 6-129059881-C-A is Benign according to our data. Variant chr6-129059881-C-A is described in ClinVar as Benign. ClinVar VariationId is 92955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.66 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4 link	c.381C>A	p.Thr127Thr	synonymous_variant	Exon 3 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 link	c.381C>A	p.Thr127Thr	synonymous_variant	Exon 3 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3 link	c.381C>A	p.Thr127Thr	synonymous_variant	Exon 3 of 65	5	NM_000426.4	ENSP00000400365.2

Frequencies

GnomAD3 genomes

AF:

0.952

AC:

144903

AN:

152158

Hom.:

69076

Cov.:

show subpopulations

Gnomad AFR

AF:

0.907

Gnomad AMI

AF:

0.992

Gnomad AMR

AF:

0.972

Gnomad ASJ

AF:

0.971

Gnomad EAS

AF:

0.972

Gnomad SAS

AF:

0.907

Gnomad FIN

AF:

0.986

Gnomad MID

AF:

0.959

Gnomad NFE

AF:

0.970

Gnomad OTH

AF:

0.961

GnomAD2 exomes

AF:

0.961

AC:

241482

AN:

251330

AF XY:

0.959

show subpopulations

Gnomad AFR exome

AF:

0.900

Gnomad AMR exome

AF:

0.984

Gnomad ASJ exome

AF:

0.972

Gnomad EAS exome

AF:

0.976

Gnomad FIN exome

AF:

0.985

Gnomad NFE exome

AF:

0.970

Gnomad OTH exome

AF:

0.965

GnomAD4 exome

AF:

0.964

AC:

1360406

AN:

1410728

Hom.:

656316

Cov.:

AF XY:

0.963

AC XY:

679017

AN XY:

705392

show subpopulations

African (AFR)

AF:

0.901

AC:

29258

AN:

32472

American (AMR)

AF:

0.983

AC:

43908

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.972

AC:

25063

AN:

25772

East Asian (EAS)

AF:

0.977

AC:

38403

AN:

39326

South Asian (SAS)

AF:

0.904

AC:

77078

AN:

85248

European-Finnish (FIN)

AF:

0.984

AC:

52527

AN:

53388

Middle Eastern (MID)

AF:

0.951

AC:

5404

AN:

5684

European-Non Finnish (NFE)

AF:

0.969

AC:

1032190

AN:

1065430

Other (OTH)

AF:

0.963

AC:

56575

AN:

58756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

2069

4138

6207

8276

10345

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20382

40764

61146

81528

101910

<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:

0.952

AC:

145022

AN:

152276

Hom.:

69134

Cov.:

AF XY:

0.953

AC XY:

70949

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.907

AC:

37673

AN:

41532

American (AMR)

AF:

0.972

AC:

14865

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.971

AC:

3373

AN:

3472

East Asian (EAS)

AF:

0.972

AC:

5033

AN:

5178

South Asian (SAS)

AF:

0.906

AC:

4378

AN:

4830

European-Finnish (FIN)

AF:

0.986

AC:

10463

AN:

10616

Middle Eastern (MID)

AF:

0.956

AC:

281

AN:

294

European-Non Finnish (NFE)

AF:

0.970

AC:

66019

AN:

68034

Other (OTH)

AF:

0.961

AC:

2032

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

340

680

1021

1361

1701

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

912

1824

2736

3648

4560

<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:

0.962

Hom.:

47411

Bravo

AF:

0.950

Asia WGS

AF:

0.932

AC:

3237

AN:

3476

EpiCase

AF:

0.969

EpiControl

AF:

0.971

ClinVar

Significance: Benign

Submissions summary: Benign:12

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 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. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 26, 2015

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

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Merosin deficient congenital muscular dystrophy

Benign:3

Apr 13, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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. -

Muscular dystrophy, limb-girdle, autosomal recessive 23

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.42

(source)

DANN

Benign

0.69

PhyloP100

-2.7

Mutation Taster

=92/8

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