chr6-129315533-A-G

Position:

chr6-129315533-A-G

Variant summary

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

The NM_000426.4(LAMA2):c.3613A>G(p.Thr1205Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00215 in 1,614,164 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 26 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 30 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.66

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047211647).

BP6

Variant 6-129315533-A-G is Benign according to our data. Variant chr6-129315533-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 129438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129315533-A-G is described in Lovd as [Benign]. Variant chr6-129315533-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0116 (1762/152292) while in subpopulation AFR AF= 0.0404 (1679/41564). AF 95% confidence interval is 0.0388. There are 26 homozygotes in gnomad4. There are 825 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 26 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4 linkuse as main transcript	c.3613A>G	p.Thr1205Ala	missense_variant	25/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 linkuse as main transcript	c.3613A>G	p.Thr1205Ala	missense_variant	25/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
LAMA2	ENST00000421865.3 linkuse as main transcript	c.3613A>G	p.Thr1205Ala	missense_variant	25/65	5	NM_000426.4	ENSP00000400365
LAMA2	ENST00000618192.5 linkuse as main transcript	c.3877A>G	p.Thr1293Ala	missense_variant	26/66	5		ENSP00000480802	P1
LAMA2	ENST00000617695.5 linkuse as main transcript	c.3613A>G	p.Thr1205Ala	missense_variant	25/64	5		ENSP00000481744

Frequencies

GnomAD3 genomes

AF:

0.0116

AC:

1765

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0406

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.00313

AC:

786

AN:

251456

Hom.:

AF XY:

0.00203

AC XY:

276

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0440

Gnomad AMR exome

AF:

0.00139

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:

0.0000615

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00117

AC:

1710

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000972

AC XY:

707

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0427

Gnomad4 AMR exome

AF:

0.00199

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.00224

GnomAD4 genome

AF:

0.0116

AC:

1762

AN:

152292

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

825

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0404

Gnomad4 AMR

AF:

0.00373

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00249

Hom.:

Bravo

AF:

0.0137

ESP6500AA

AF:

0.0402

AC:

177

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00406

AC:

493

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 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. -
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	PreventionGenetics, part of Exact Sciences	-	- -

LAMA2-related muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Congenital muscular dystrophy due to partial LAMA2 deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.011

.;T;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.75

T;T;T

MetaRNN

Benign

0.0047

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

.;.;M

MutationTaster

Benign

0.96

PrimateAI

Benign

0.35

PROVEAN

Benign

0.39

.;.;N

REVEL

Benign

0.088

Sift

Benign

0.11

.;.;T

Polyphen

0.087

.;.;B

Vest4

0.50

MVP

0.47

MPC

0.10

ClinPred

0.025

GERP RS

4.7

Varity_R

0.15

gMVP

0.59

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