6-129481381-T-C

Position:

chr6-129481381-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_StrongPP5

The NM_000426.4(LAMA2):c.7691T>C(p.Leu2564Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 7.50

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 6-129481381-T-C is Pathogenic according to our data. Variant chr6-129481381-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14294.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}. Variant chr6-129481381-T-C is described in Lovd as [Pathogenic]. Variant chr6-129481381-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LAMA2	NM_000426.4 linkuse as main transcript	c.7691T>C	p.Leu2564Pro	missense_variant	55/65	ENST00000421865.3
LOC124901401	XR_007059767.1 linkuse as main transcript	n.5002A>G		non_coding_transcript_exon_variant	2/2
LAMA2	NM_001079823.2 linkuse as main transcript	c.7679T>C	p.Leu2560Pro	missense_variant	54/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE
LAMA2	ENST00000421865.3 linkuse as main transcript	c.7691T>C	p.Leu2564Pro	missense_variant	55/65	5	NM_000426.4
	ENST00000442449.1 linkuse as main transcript	n.30A>G		non_coding_transcript_exon_variant	1/2	5
	ENST00000665046.1 linkuse as main transcript	n.975+21224A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461702

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Merosin deficient congenital muscular dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 09, 2001	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 08, 2023

Variant summary: LAMA2 c.7691T>C (p.Leu2564Pro) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the Laminin G domain (IPR001791) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251280 control chromosomes (gnomAD). c.7691T>C has been reported in the literature in an individual affected with Laminin Alpha 2-Related Dystrophy who was compound heterozygous with a likely pathogenic variant (He_2001, Punetha_2016, O'Grady_2016). These data suggest the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11591858, 27854218, 27159402). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.082

.;T;D

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.65

MutationAssessor

Uncertain

2.8

.;.;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.9

.;.;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

.;.;D

Polyphen

1.0

.;.;D

Vest4

0.92

MutPred

0.90

.;.;Gain of disorder (P = 0.0052);

MVP

0.94

MPC

0.61

ClinPred

1.0

GERP RS

5.2

Varity_R

0.95

gMVP

0.97

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over