rs56209257

Positions:

chr6-129456415-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000426.4(LAMA2):c.6788C>T(p.Thr2263Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000607 in 1,613,358 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 2 hom. )

Consequence

LAMA2
NM_000426.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0180

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 6-129456415-C-T is Benign according to our data. Variant chr6-129456415-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 355292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00283 (431/152238) while in subpopulation AFR AF= 0.00962 (400/41562). AF 95% confidence interval is 0.00885. There are 3 homozygotes in gnomad4. There are 229 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4 linkuse as main transcript	c.6788C>T	p.Thr2263Met	missense_variant	48/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 linkuse as main transcript	c.6788C>T	p.Thr2263Met	missense_variant	48/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3 linkuse as main transcript	c.6788C>T	p.Thr2263Met	missense_variant	48/65	5	NM_000426.4	ENSP00000400365
	ENST00000665046.1 linkuse as main transcript	n.976-15163G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00277

AC:

422

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00944

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000852

AC:

214

AN:

251122

Hom.:

AF XY:

0.000685

AC XY:

AN XY:

135724

show subpopulations

Gnomad AFR exome

AF:

0.00954

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000376

AC:

549

AN:

1461120

Hom.:

Cov.:

AF XY:

0.000365

AC XY:

265

AN XY:

726908

show subpopulations

Gnomad4 AFR exome

AF:

0.00858

Gnomad4 AMR exome

AF:

0.000716

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000148

Gnomad4 OTH exome

AF:

0.000845

GnomAD4 genome

AF:

0.00283

AC:

431

AN:

152238

Hom.:

Cov.:

AF XY:

0.00308

AC XY:

229

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00962

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000468

Hom.:

Bravo

AF:

0.00300

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000964

AC:

117

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	LAMA2: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2019	This variant is associated with the following publications: (PMID: 30055037) -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 23, 2021

- -

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

Benign

0.071

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.023

.;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.57

T;T;T

MetaRNN

Benign

0.0080

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.83

.;.;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.1

.;.;N

REVEL

Benign

0.23

Sift

Benign

0.11

.;.;T

Polyphen

0.87

.;.;P

Vest4

0.13

MVP

0.57

MPC

0.17

ClinPred

0.021

GERP RS

-6.4

Varity_R

0.021

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.34

Position offset: 12

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