6-129401308-C-A

Position:

chr6-129401308-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000426.4(LAMA2):c.5530C>A(p.Arg1844Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,610,812 control chromosomes in the GnomAD database, including 250 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1844H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.010 ( 9 hom., cov: 33)

Exomes 𝑓: 0.016 ( 241 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 0.873

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045015514).

BP6

Variant 6-129401308-C-A is Benign according to our data. Variant chr6-129401308-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92968.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=6, Uncertain_significance=1}. Variant chr6-129401308-C-A is described in Lovd as [Benign]. Variant chr6-129401308-C-A is described in Lovd as [Likely_benign]. Variant chr6-129401308-C-A is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.01 (1524/152248) while in subpopulation NFE AF= 0.0175 (1190/68006). AF 95% confidence interval is 0.0167. There are 9 homozygotes in gnomad4. There are 682 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4 linkuse as main transcript	c.5530C>A	p.Arg1844Ser	missense_variant	38/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 linkuse as main transcript	c.5530C>A	p.Arg1844Ser	missense_variant	38/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
LAMA2	ENST00000421865.3 linkuse as main transcript	c.5530C>A	p.Arg1844Ser	missense_variant	38/65	5	NM_000426.4	ENSP00000400365
LAMA2	ENST00000618192.5 linkuse as main transcript	c.5794C>A	p.Arg1932Ser	missense_variant	39/66	5		ENSP00000480802	P1
LAMA2	ENST00000617695.5 linkuse as main transcript	c.5530C>A	p.Arg1844Ser	missense_variant	38/64	5		ENSP00000481744

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

1525

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00290

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00871

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00415

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0175

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.0104

AC:

2604

AN:

250736

Hom.:

AF XY:

0.0106

AC XY:

1442

AN XY:

135504

show subpopulations

Gnomad AFR exome

AF:

0.00339

Gnomad AMR exome

AF:

0.00593

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00323

Gnomad FIN exome

AF:

0.00483

Gnomad NFE exome

AF:

0.0184

Gnomad OTH exome

AF:

0.00900

GnomAD4 exome

AF:

0.0160

AC:

23366

AN:

1458564

Hom.:

241

Cov.:

AF XY:

0.0157

AC XY:

11428

AN XY:

725826

show subpopulations

Gnomad4 AFR exome

AF:

0.00234

Gnomad4 AMR exome

AF:

0.00566

Gnomad4 ASJ exome

AF:

0.000192

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00350

Gnomad4 FIN exome

AF:

0.00581

Gnomad4 NFE exome

AF:

0.0196

Gnomad4 OTH exome

AF:

0.0106

GnomAD4 genome

AF:

0.0100

AC:

1524

AN:

152248

Hom.:

Cov.:

AF XY:

0.00916

AC XY:

682

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00289

Gnomad4 AMR

AF:

0.00869

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.00415

Gnomad4 NFE

AF:

0.0175

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.0155

Hom.:

Bravo

AF:

0.00971

TwinsUK

AF:

0.0205

AC:

ALSPAC

AF:

0.0153

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0171

AC:

147

ExAC

AF:

0.0107

AC:

1297

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0152

EpiControl

AF:

0.0142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

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)	Oct 04, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 17, 2022	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2019	This variant is associated with the following publications: (PMID: 20207543, 9541105, 25256590, 27535533, 29706646) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	LAMA2: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 11, 2015	- -

Polymicrogyria

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Sep 01, 2017

this variant was indentified in an individual with malformations of cortical development -

Merosin deficient congenital muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The heterozygous p.Arg1844Ser variant in LAMA2 has been reported in the compound heterozygous state, with a splice site mutation, in an individual with congenital muscular dystrophy (PMID: 20207543), but has also been identified in >1% of European (non-Finnish) chromosomes and 18 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive congenital muscular dystrophy. -

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

Mar 08, 2018

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

0.11

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.011

.;T;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.80

T;T;T

MetaRNN

Benign

0.0045

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.7

.;.;L

MutationTaster

Benign

0.97

PrimateAI

Benign

0.23

PROVEAN

Benign

0.71

.;.;N

REVEL

Benign

0.035

Sift

Benign

0.73

.;.;T

Polyphen

0.085

.;.;B

Vest4

0.21

MPC

0.11

ClinPred

0.0062

GERP RS

4.4

Varity_R

0.13

gMVP

0.20

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