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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Myriad Women’s Health
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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000426.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	NM_000426.4	MANE Select	c.74C>T	p.Pro25Leu	missense	Exon 1 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.74C>T	p.Pro25Leu	missense	Exon 1 of 64	NP_001073291.2	A0A087WYF1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LAMA2	ENST00000421865.3	TSL:5 MANE Select	c.74C>T	p.Pro25Leu	missense	Exon 1 of 65	ENSP00000400365.2	P24043
LAMA2	ENST00000618192.5	TSL:5	c.74C>T	p.Pro25Leu	missense	Exon 1 of 66	ENSP00000480802.2	A0A087WX80
LAMA2	ENST00000617695.5	TSL:5	c.74C>T	p.Pro25Leu	missense	Exon 1 of 64	ENSP00000481744.2	A0A087WYF1

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Congenital muscular dystrophy due to partial LAMA2 deficiency (1)

Inborn genetic diseases (1)

LAMA2-related disorder (1)

LAMA2-related muscular dystrophy (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0048

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PhyloP100

-0.51

PrimateAI

Benign

0.40

PROVEAN

Benign

0.060

REVEL

Benign

0.029

Sift

Benign

0.29

Polyphen

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over