rs36044314

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_000426.4(LAMA2):c.1798G>A(p.Gly600Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0177 in 1,601,344 control chromosomes in the GnomAD database, including 329 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 29 hom., cov: 32)

Exomes 𝑓: 0.018 ( 300 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 6.08

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, PROVEAN [when BayesDel_addAF, BayesDel_noAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.008395851).

BP6

Variant 6-129250127-G-A is Benign according to our data. Variant chr6-129250127-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129250127-G-A is described in Lovd as [Benign]. Variant chr6-129250127-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0129 (1958/152228) while in subpopulation SAS AF= 0.02 (96/4810). AF 95% confidence interval is 0.0184. There are 29 homozygotes in gnomad4. There are 929 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 29 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4 linkuse as main transcript	c.1798G>A	p.Gly600Arg	missense_variant	13/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 linkuse as main transcript	c.1798G>A	p.Gly600Arg	missense_variant	13/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LAMA2	ENST00000421865.3 linkuse as main transcript	c.1798G>A	p.Gly600Arg	missense_variant	13/65	5	NM_000426.4	ENSP00000400365.2	P24043
LAMA2	ENST00000618192.5 linkuse as main transcript	c.1798G>A	p.Gly600Arg	missense_variant	13/66	5		ENSP00000480802.2	A0A087WX80
LAMA2	ENST00000617695.5 linkuse as main transcript	c.1798G>A	p.Gly600Arg	missense_variant	13/64	5		ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1956

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00304

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0118

Gnomad ASJ

AF:

0.0233

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0195

Gnomad FIN

AF:

0.00998

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0193

Gnomad OTH

AF:

0.0167

GnomAD3 exomes

AF:

0.0139

AC:

3479

AN:

251146

Hom.:

AF XY:

0.0144

AC XY:

1960

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.00363

Gnomad AMR exome

AF:

0.00847

Gnomad ASJ exome

AF:

0.0281

Gnomad EAS exome

AF:

0.000708

Gnomad SAS exome

AF:

0.0163

Gnomad FIN exome

AF:

0.00873

Gnomad NFE exome

AF:

0.0181

Gnomad OTH exome

AF:

0.0147

GnomAD4 exome

AF:

0.0182

AC:

26388

AN:

1449116

Hom.:

300

Cov.:

AF XY:

0.0184

AC XY:

13286

AN XY:

721918

show subpopulations

Gnomad4 AFR exome

AF:

0.00338

Gnomad4 AMR exome

AF:

0.00879

Gnomad4 ASJ exome

AF:

0.0254

Gnomad4 EAS exome

AF:

0.000682

Gnomad4 SAS exome

AF:

0.0158

Gnomad4 FIN exome

AF:

0.00825

Gnomad4 NFE exome

AF:

0.0202

Gnomad4 OTH exome

AF:

0.0167

GnomAD4 genome

AF:

0.0129

AC:

1958

AN:

152228

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

929

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00303

Gnomad4 AMR

AF:

0.0118

Gnomad4 ASJ

AF:

0.0233

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0200

Gnomad4 FIN

AF:

0.00998

Gnomad4 NFE

AF:

0.0193

Gnomad4 OTH

AF:

0.0166

Alfa

AF:

0.0188

Hom.:

Bravo

AF:

0.0124

TwinsUK

AF:

0.0165

AC:

ALSPAC

AF:

0.0187

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0206

AC:

177

ExAC

AF:

0.0132

AC:

1604

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.0212

EpiControl

AF:

0.0187

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 08, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 19, 2015	- -

not provided

Benign:4

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	Aug 01, 2024	LAMA2: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.071

.;T;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

D;D;D

MetaRNN

Benign

0.0084

T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Pathogenic

3.1

.;.;M

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-6.6

.;.;D

REVEL

Uncertain

0.39

Sift

Benign

0.031

.;.;D

Polyphen

1.0

.;.;D

Vest4

0.68

MutPred

0.93

Loss of catalytic residue at P596 (P = 0.0966);Loss of catalytic residue at P596 (P = 0.0966);Loss of catalytic residue at P596 (P = 0.0966);

MPC

0.51

ClinPred

0.029

GERP RS

5.7

Varity_R

0.89

gMVP

0.89

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