rs149165006

Positions:

chr6-129300852-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000426.4(LAMA2):c.3154A>G(p.Ser1052Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000105 in 1,613,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.00058 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 4.97

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 Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020792753).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4 linkuse as main transcript	c.3154A>G	p.Ser1052Gly	missense_variant	22/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 linkuse as main transcript	c.3154A>G	p.Ser1052Gly	missense_variant	22/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LAMA2	ENST00000421865.3 linkuse as main transcript	c.3154A>G	p.Ser1052Gly	missense_variant	22/65	5	NM_000426.4	ENSP00000400365.2	P24043
LAMA2	ENST00000618192.5 linkuse as main transcript	c.3418A>G	p.Ser1140Gly	missense_variant	23/66	5		ENSP00000480802.2	A0A087WX80
LAMA2	ENST00000617695.5 linkuse as main transcript	c.3154A>G	p.Ser1052Gly	missense_variant	22/64	5		ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes

AF:

0.000578

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251456

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000554

AC:

AN:

1461560

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.00206

Gnomad4 AMR exome

AF:

0.0000447

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000578

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00209

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000454

Hom.:

Bravo

AF:

0.000593

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000189

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 27, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2017	The S1052G variant has been previously reported in an individual with congenital muscular dystrophy who harbored an additional LAMA2 variant; however, segregation analysis to determine phase was not reported (Valencia et al., 2013). The S1052G variant is observed in 22/10,404 (0.21%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals; however, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with LAMA2-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. -

LAMA2-related muscular dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

LAMA2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.028

.;T;T

Eigen

Benign

0.020

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.78

T;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.085

.;.;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.2

.;.;N

REVEL

Benign

0.13

Sift

Benign

0.072

.;.;T

Polyphen

0.32

.;.;B

Vest4

0.31

MVP

0.69

MPC

0.16

ClinPred

0.076

GERP RS

4.4

Varity_R

0.12

gMVP

0.31

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