6-129369987-C-G

Variant names:

• chr6-129369987-C-G
• rs17057184
• NM_000426.4:c.4956C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000426.4(LAMA2):​c.4956C>G​(p.Thr1652Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0667 in 1,613,146 control chromosomes in the GnomAD database, including 4,638 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. T1652T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.081 (612 hom., cov: 32)
  • Exomes 𝑓: 0.065 (4026 hom.)
• Consequence: LAMA2 NM_000426.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.45
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• congenital merosin-deficient muscular dystrophy 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
• LAMA2-related muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy, limb-girdle, autosomal recessive 23

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 6-129369987-C-G is Benign according to our data. Variant chr6-129369987-C-G is described in ClinVar as Benign. ClinVar VariationId is 92963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.45 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000426.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	NM_000426.4	MANE Select	c.4956C>G	p.Thr1652Thr	synonymous	Exon 34 of 65	NP_000417.3
	LAMA2	NM_001079823.2		c.4956C>G	p.Thr1652Thr	synonymous	Exon 34 of 64	NP_001073291.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA2	ENST00000421865.3	TSL:5 MANE Select	c.4956C>G	p.Thr1652Thr	synonymous	Exon 34 of 65	ENSP00000400365.2
	LAMA2	ENST00000618192.5	TSL:5	c.5220C>G	p.Thr1740Thr	synonymous	Exon 35 of 66	ENSP00000480802.2
	LAMA2	ENST00000617695.5	TSL:5	c.4956C>G	p.Thr1652Thr	synonymous	Exon 34 of 64	ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.0812 AC: 12345 AN: 152054 Hom.: 608 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.0850

Gnomad EAS AF: 0.0350

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0517

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0572

Gnomad OTH AF: 0.0934

GnomAD2 exomes AF: 0.0887 AC: 22204 AN: 250462 AF XY: 0.0879

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.0845

Gnomad EAS exome AF: 0.0305

Gnomad FIN exome AF: 0.0487

Gnomad NFE exome AF: 0.0604

Gnomad OTH exome AF: 0.0876

GnomAD4 exome AF: 0.0651 AC: 95146 AN: 1460974 Hom.: 4026 Cov.: 31 AF XY: 0.0669 AC XY: 48639 AN XY: 726822

African (AFR) AF: 0.112 AC: 3740 AN: 33436

American (AMR) AF: 0.185 AC: 8252 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0880 AC: 2298 AN: 26126

East Asian (EAS) AF: 0.0298 AC: 1183 AN: 39684

South Asian (SAS) AF: 0.131 AC: 11294 AN: 86216

European-Finnish (FIN) AF: 0.0502 AC: 2681 AN: 53386

Middle Eastern (MID) AF: 0.116 AC: 666 AN: 5766

European-Non Finnish (NFE) AF: 0.0543 AC: 60376 AN: 1111290

Other (OTH) AF: 0.0771 AC: 4656 AN: 60364

GnomAD4 genome AF: 0.0813 AC: 12373 AN: 152172 Hom.: 612 Cov.: 32 AF XY: 0.0824 AC XY: 6126 AN XY: 74388

African (AFR) AF: 0.109 AC: 4507 AN: 41512

American (AMR) AF: 0.140 AC: 2138 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0850 AC: 295 AN: 3470

East Asian (EAS) AF: 0.0349 AC: 181 AN: 5182

South Asian (SAS) AF: 0.119 AC: 575 AN: 4818

European-Finnish (FIN) AF: 0.0517 AC: 548 AN: 10592

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0572 AC: 3891 AN: 68010

Other (OTH) AF: 0.0943 AC: 199 AN: 2110

Alfa AF: 0.0678 Hom.: 133

Bravo AF: 0.0884

Asia WGS AF: 0.108 AC: 362 AN: 3372

EpiCase AF: 0.0634

EpiControl AF: 0.0691

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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.

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 21, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

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

Merosin deficient congenital muscular dystrophy Benign:1

Apr 13, 2017

Athena Diagnostics

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 12, 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.0
DANN	Benign	0.56
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs17057184; hg19: chr6-129691132;