6-129492030-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000426.4(LAMA2):c.8028T>C(p.Asn2676Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,614,016 control chromosomes in the GnomAD database, including 260 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 63 hom., cov: 32)

Exomes 𝑓: 0.014 ( 197 hom. )

Consequence

LAMA2
NM_000426.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.466

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:

ENSG00000226149 (HGNC:):

ENSG00000226149 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=-0.56).

BP6

Variant 6-129492030-T-C is Benign according to our data. Variant chr6-129492030-T-C is described in ClinVar as Benign. ClinVar VariationId is 129443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.466 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0216 (3291/152274) while in subpopulation AFR AF = 0.0485 (2016/41530). AF 95% confidence interval is 0.0468. There are 63 homozygotes in GnomAd4. There are 1517 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 63 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4 link	c.8028T>C	p.Asn2676Asn	synonymous_variant	Exon 57 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 link	c.8016T>C	p.Asn2672Asn	synonymous_variant	Exon 56 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3 link	c.8028T>C	p.Asn2676Asn	synonymous_variant	Exon 57 of 65	5	NM_000426.4	ENSP00000400365.2		P24043

Frequencies

GnomAD3 genomes

AF:

0.0215

AC:

3265

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0480

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00405

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0141

Gnomad OTH

AF:

0.0230

GnomAD2 exomes

AF:

0.0122

AC:

3056

AN:

251250

AF XY:

0.0113

show subpopulations

Gnomad AFR exome

AF:

0.0501

Gnomad AMR exome

AF:

0.00688

Gnomad ASJ exome

AF:

0.00834

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00559

Gnomad NFE exome

AF:

0.0144

Gnomad OTH exome

AF:

0.0139

GnomAD4 exome

AF:

0.0137

AC:

20018

AN:

1461742

Hom.:

197

Cov.:

AF XY:

0.0135

AC XY:

9781

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.0516

AC:

1726

AN:

33470

American (AMR)

AF:

0.00830

AC:

371

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00685

AC:

179

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39674

South Asian (SAS)

AF:

0.00245

AC:

211

AN:

86256

European-Finnish (FIN)

AF:

0.00672

AC:

359

AN:

53420

Middle Eastern (MID)

AF:

0.00884

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0145

AC:

16145

AN:

1111902

Other (OTH)

AF:

0.0161

AC:

975

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1039

2079

3118

4158

5197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

616

1232

1848

2464

3080

<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:

0.0216

AC:

3291

AN:

152274

Hom.:

Cov.:

AF XY:

0.0204

AC XY:

1517

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0485

AC:

2016

AN:

41530

American (AMR)

AF:

0.0122

AC:

186

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00249

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00405

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0141

AC:

960

AN:

68016

Other (OTH)

AF:

0.0227

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

160

321

481

642

802

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0175

Hom.:

Bravo

AF:

0.0234

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0125

EpiControl

AF:

0.0116

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Feb 29, 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. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Merosin deficient congenital muscular dystrophy

Benign:1

Jun 27, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

not provided

Benign:1

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

1.7

(source)

DANN

Benign

0.72

PhyloP100

-0.47

Mutation Taster

=100/0

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