rs117781224

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000426.4(LAMA2):c.4750G>A(p.Gly1584Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,613,708 control chromosomes in the GnomAD database, including 802 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 43 hom., cov: 31)

Exomes 𝑓: 0.029 ( 759 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.15

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:

LAMA2 (HGNC:):

LAMA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008308321).

BP6

Variant 6-129366251-G-A is Benign according to our data. Variant chr6-129366251-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129366251-G-A is described in Lovd as [Pathogenic]. Variant chr6-129366251-G-A is described in Lovd as [Likely_benign]. Variant chr6-129366251-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0191 (2908/151944) while in subpopulation NFE AF= 0.0306 (2081/67942). AF 95% confidence interval is 0.0295. There are 43 homozygotes in gnomad4. There are 1368 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 43 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4 linkuse as main transcript	c.4750G>A	p.Gly1584Ser	missense_variant	33/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 linkuse as main transcript	c.4750G>A	p.Gly1584Ser	missense_variant	33/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3 linkuse as main transcript	c.4750G>A	p.Gly1584Ser	missense_variant	33/65	5	NM_000426.4	ENSP00000400365.2		P24043

Frequencies

GnomAD3 genomes

AF:

0.0191

AC:

2907

AN:

151826

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00631

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0205

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00984

Gnomad FIN

AF:

0.00824

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0306

Gnomad OTH

AF:

0.0202

GnomAD3 exomes

AF:

0.0195

AC:

4888

AN:

251002

Hom.:

AF XY:

0.0199

AC XY:

2701

AN XY:

135632

show subpopulations

Gnomad AFR exome

AF:

0.00578

Gnomad AMR exome

AF:

0.0114

Gnomad ASJ exome

AF:

0.0230

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0123

Gnomad FIN exome

AF:

0.0115

Gnomad NFE exome

AF:

0.0302

Gnomad OTH exome

AF:

0.0199

GnomAD4 exome

AF:

0.0295

AC:

43091

AN:

1461764

Hom.:

759

Cov.:

AF XY:

0.0288

AC XY:

20937

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00499

Gnomad4 AMR exome

AF:

0.0119

Gnomad4 ASJ exome

AF:

0.0205

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0122

Gnomad4 FIN exome

AF:

0.0126

Gnomad4 NFE exome

AF:

0.0345

Gnomad4 OTH exome

AF:

0.0265

GnomAD4 genome

AF:

0.0191

AC:

2908

AN:

151944

Hom.:

Cov.:

AF XY:

0.0184

AC XY:

1368

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.00629

Gnomad4 AMR

AF:

0.0206

Gnomad4 ASJ

AF:

0.0202

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.0101

Gnomad4 FIN

AF:

0.00824

Gnomad4 NFE

AF:

0.0306

Gnomad4 OTH

AF:

0.0199

Alfa

AF:

0.0279

Hom.:

124

Bravo

AF:

0.0193

TwinsUK

AF:

0.0337

AC:

125

ALSPAC

AF:

0.0330

AC:

127

ESP6500AA

AF:

0.00840

AC:

ESP6500EA

AF:

0.0330

AC:

284

ExAC

AF:

0.0196

AC:

2382

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2012	- -

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	LAMA2: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

LAMA2-related muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Congenital muscular dystrophy due to partial LAMA2 deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.012

.;T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.62

T;T;T

MetaRNN

Benign

0.0083

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

.;.;L

PrimateAI

Benign

0.34

PROVEAN

Benign

0.080

.;.;N

REVEL

Benign

0.090

Sift

Benign

0.26

.;.;T

Polyphen

0.013

.;.;B

Vest4

0.19

MPC

0.088

ClinPred

0.0081

GERP RS

3.5

Varity_R

0.038

gMVP

0.73

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