rs201375881

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000426.4(LAMA2):c.9211+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,607,204 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 6 hom. )

Consequence

LAMA2
NM_000426.4 splice_region, intron

Scores

Splicing: ADA: 0.006916

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:9

Conservation

PhyloP100: 0.0170

Publications

2 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:

ENSG00000226149 (HGNC:):

ENSG00000226149 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 6-129514601-T-C is Benign according to our data. Variant chr6-129514601-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 162583.

BS2

High Homozygotes in GnomAdExome4 at 6 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.9211+6T>C		splice_region intron	N/A	NP_000417.3
	LAMA2	NM_001079823.2		c.9199+6T>C		splice_region intron	N/A	NP_001073291.2	A0A087WYF1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LAMA2	ENST00000421865.3	TSL:5 MANE Select	c.9211+6T>C	splice_region intron	N/A	ENSP00000400365.2	P24043
LAMA2	ENST00000618192.5	TSL:5	c.9475+6T>C	splice_region intron	N/A	ENSP00000480802.2	A0A087WX80
LAMA2	ENST00000617695.5	TSL:5	c.9199+6T>C	splice_region intron	N/A	ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes

AF:

0.000848

AC:

129

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00166

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000701

AC:

176

AN:

251034

AF XY:

0.000707

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00148

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00178

AC:

2583

AN:

1454912

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

1216

AN XY:

724300

show subpopulations

African (AFR)

AF:

0.000240

AC:

AN:

33326

American (AMR)

AF:

0.0000224

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39624

South Asian (SAS)

AF:

0.00

AC:

AN:

86106

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5486

European-Non Finnish (NFE)

AF:

0.00227

AC:

2514

AN:

1106012

Other (OTH)

AF:

0.000881

AC:

AN:

60166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

117

235

352

470

587

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<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:

0.000847

AC:

129

AN:

152292

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41556

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00166

AC:

113

AN:

68036

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00137

Hom.:

Bravo

AF:

0.000790

EpiCase

AF:

0.00109

EpiControl

AF:

0.00136

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Congenital muscular dystrophy due to partial LAMA2 deficiency (1)

Inborn genetic diseases (1)

LAMA2-related muscular dystrophy (1)

Merosin deficient congenital muscular dystrophy (1)

Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

9.7

(source)

DANN

Benign

0.64

PhyloP100

0.017

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0069

dbscSNV1_RF

Benign

0.63

SpliceAI score (max)

0.030

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