6-128883319-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000426.4(LAMA2):c.74C>T(p.Pro25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,598,086 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -0.512

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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004836589).

BP6

Variant 6-128883319-C-T is Benign according to our data. Variant chr6-128883319-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 381265.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00166 (252/152258) while in subpopulation AFR AF = 0.00546 (227/41552). AF 95% confidence interval is 0.00488. There are 2 homozygotes in GnomAd4. There are 107 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4 link	c.74C>T	p.Pro25Leu	missense_variant	Exon 1 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 link	c.74C>T	p.Pro25Leu	missense_variant	Exon 1 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3 link	c.74C>T	p.Pro25Leu	missense_variant	Exon 1 of 65	5	NM_000426.4	ENSP00000400365.2		P24043

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

250

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00548

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000416

AC:

AN:

218500

AF XY:

0.000305

show subpopulations

Gnomad AFR exome

AF:

0.00532

Gnomad AMR exome

AF:

0.000527

Gnomad ASJ exome

AF:

0.000106

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000311

Gnomad OTH exome

AF:

0.000183

GnomAD4 exome

AF:

0.000205

AC:

297

AN:

1445828

Hom.:

Cov.:

AF XY:

0.000184

AC XY:

132

AN XY:

717284

show subpopulations

African (AFR)

AF:

0.00602

AC:

200

AN:

33250

American (AMR)

AF:

0.000466

AC:

AN:

42906

Ashkenazi Jewish (ASJ)

AF:

0.000233

AC:

AN:

25806

East Asian (EAS)

AF:

0.00

AC:

AN:

39106

South Asian (SAS)

AF:

0.0000240

AC:

AN:

83404

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51124

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000199

AC:

AN:

1104688

Other (OTH)

AF:

0.000619

AC:

AN:

59798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00166

AC:

252

AN:

152258

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00546

AC:

227

AN:

41552

American (AMR)

AF:

0.00118

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68018

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000426

Hom.:

Bravo

AF:

0.00176

ESP6500AA

AF:

0.00394

AC:

ESP6500EA

AF:

0.000236

AC:

ExAC

AF:

0.000390

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 10, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 27, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LAMA2: BP4 -

Congenital muscular dystrophy due to partial LAMA2 deficiency

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:1

Mar 11, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LAMA2 c.74C>T (p.Pro25Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 1591136 control chromosomes, predominantly at a frequency of 0.0057 within the African or African-American subpopulation in the gnomAD database (v4.1 dataset), including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.61 fold of the estimated maximal expected allele frequency for a pathogenic variant in LAMA2 causing Merosin deficient congenital muscular dystrophy phenotype (0.0035). To our knowledge, no occurrence of c.74C>T in individuals affected with Merosin deficient congenital muscular dystrophy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 381265). Based on the evidence outlined above, the variant was classified as likely benign. -

Inborn genetic diseases

Benign:1

Apr 25, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

LAMA2-related muscular dystrophy

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

LAMA2-related disorder

Benign:1

Apr 23, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

7.4

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.011

.;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.56

T;T;T

MetaRNN

Benign

0.0048

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

.;.;N

PhyloP100

-0.51

PrimateAI

Benign

0.40

PROVEAN

Benign

0.060

.;.;N

REVEL

Benign

0.029

Sift

Benign

0.29

.;.;T

Polyphen

0.0

.;.;B

Vest4

0.13

MVP

0.45

MPC

0.090

ClinPred

0.0093

GERP RS

1.2

PromoterAI

-0.13

Neutral

(source)

Varity_R

0.028

gMVP

0.23

Mutation Taster

=96/4

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over