6-129049961-C-T

Variant names:

• chr6-129049961-C-T
• rs1140366
• NM_000426.4:c.156C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000426.4(LAMA2):​c.156C>T​(p.Ile52Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,613,378 control chromosomes in the GnomAD database, including 9,220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (708 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8512 hom.)
• Consequence: LAMA2 NM_000426.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.47

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 6-129049961-C-T is Benign according to our data. Variant chr6-129049961-C-T is described in ClinVar as [Benign]. Clinvar id is 92938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129049961-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.156C>T	p.Ile52Ile	synonymous_variant	Exon 2 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.156C>T	p.Ile52Ile	synonymous_variant	Exon 2 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.156C>T	p.Ile52Ile	synonymous_variant	Exon 2 of 65	5	NM_000426.4	ENSP00000400365.2

Frequencies

GnomAD3 genomes AF: 0.0847 AC: 12879 AN: 152030 Hom.: 709 Cov.: 32

Gnomad AFR AF: 0.0182

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.0811

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.0549

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.0917

GnomAD3 exomes AF: 0.0985 AC: 24764 AN: 251472 Hom.: 1415 AF XY: 0.101 AC XY: 13686 AN XY: 135912

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.0649

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.150

Gnomad SAS exome AF: 0.0551

Gnomad FIN exome AF: 0.0953

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.104 AC: 151994 AN: 1461230 Hom.: 8512 Cov.: 32 AF XY: 0.104 AC XY: 75563 AN XY: 727000

Gnomad4 AFR exome AF: 0.0173

Gnomad4 AMR exome AF: 0.0669

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.170

Gnomad4 SAS exome AF: 0.0580

Gnomad4 FIN exome AF: 0.0957

Gnomad4 NFE exome AF: 0.108

Gnomad4 OTH exome AF: 0.103

GnomAD4 genome AF: 0.0847 AC: 12883 AN: 152148 Hom.: 708 Cov.: 32 AF XY: 0.0829 AC XY: 6165 AN XY: 74370

Gnomad4 AFR AF: 0.0181

Gnomad4 AMR AF: 0.0809

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.155

Gnomad4 SAS AF: 0.0552

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.0931

Alfa AF: 0.104 Hom.: 1016

Bravo AF: 0.0827

Asia WGS AF: 0.107 AC: 372 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 20, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Merosin deficient congenital muscular dystrophy Benign:2

Apr 13, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LAMA2-related muscular dystrophy Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital muscular dystrophy due to partial LAMA2 deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	9.3
DANN	Benign	0.81

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: rs1140366; hg19: chr6-129371106; COSMIC: COSV70340933;