rs4404787

chr6-129059881-C-Achr6-129059881-C-Gchr6-129059881-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000426.4(LAMA2):c.381C>A(p.Thr127=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.963 in 1,563,004 control chromosomes in the GnomAD database, including 725,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T127T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.95 (69134 hom., cov: 32)
  • Exomes 𝑓: 0.96 (656316 hom.)
• Consequence: LAMA2 NM_000426.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.66

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 6-129059881-C-A is Benign according to our data. Variant chr6-129059881-C-A is described in ClinVar as [Benign]. Clinvar id is 92955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129059881-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.66 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.381C>A	p.Thr127=	synonymous_variant	3/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.381C>A	p.Thr127=	synonymous_variant	3/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.381C>A	p.Thr127=	synonymous_variant	3/65	5	NM_000426.4

Frequencies

GnomAD3 genomes AF: 0.952 AC: 144903 AN: 152158 Hom.: 69076 Cov.: 32

Gnomad AFR AF: 0.907

Gnomad AMI AF: 0.992

Gnomad AMR AF: 0.972

Gnomad ASJ AF: 0.971

Gnomad EAS AF: 0.972

Gnomad SAS AF: 0.907

Gnomad FIN AF: 0.986

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.970

Gnomad OTH AF: 0.961

GnomAD3 exomes AF: 0.961 AC: 241482 AN: 251330 Hom.: 116164 AF XY: 0.959 AC XY: 130193 AN XY: 135824

Gnomad AFR exome AF: 0.900

Gnomad AMR exome AF: 0.984

Gnomad ASJ exome AF: 0.972

Gnomad EAS exome AF: 0.976

Gnomad SAS exome AF: 0.903

Gnomad FIN exome AF: 0.985

Gnomad NFE exome AF: 0.970

Gnomad OTH exome AF: 0.965

GnomAD4 exome AF: 0.964 AC: 1360406 AN: 1410728 Hom.: 656316 Cov.: 23 AF XY: 0.963 AC XY: 679017 AN XY: 705392

Gnomad4 AFR exome AF: 0.901

Gnomad4 AMR exome AF: 0.983

Gnomad4 ASJ exome AF: 0.972

Gnomad4 EAS exome AF: 0.977

Gnomad4 SAS exome AF: 0.904

Gnomad4 FIN exome AF: 0.984

Gnomad4 NFE exome AF: 0.969

Gnomad4 OTH exome AF: 0.963

GnomAD4 genome AF: 0.952 AC: 145022 AN: 152276 Hom.: 69134 Cov.: 32 AF XY: 0.953 AC XY: 70949 AN XY: 74462

Gnomad4 AFR AF: 0.907

Gnomad4 AMR AF: 0.972

Gnomad4 ASJ AF: 0.971

Gnomad4 EAS AF: 0.972

Gnomad4 SAS AF: 0.906

Gnomad4 FIN AF: 0.986

Gnomad4 NFE AF: 0.970

Gnomad4 OTH AF: 0.961

Alfa AF: 0.961 Hom.: 37299

Bravo AF: 0.950

Asia WGS AF: 0.932 AC: 3237 AN: 3476

EpiCase AF: 0.969

EpiControl AF: 0.971

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 26, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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. -

Merosin deficient congenital muscular dystrophy Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 13, 2017	- -

LAMA2-related muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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

Muscular dystrophy, limb-girdle, autosomal recessive 23 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	0.42
Dann	Benign	0.69

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

Other links and lift over

dbSNP: rs4404787; hg19: chr6-129381026;