rs142451929

Variant names:

• chr6-129505238-T-C
• rs142451929
• NM_000426.4:c.8586T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-129505238-T-C
• chr6-129505238-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000426.4(LAMA2):​c.8586T>C​(p.Tyr2862Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000712 in 1,613,948 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00077 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (2 hom.)
• Consequence: LAMA2 NM_000426.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.206

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]

ENSG00000226149 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-129505238-T-C is Benign according to our data. Variant chr6-129505238-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 256090.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}. Variant chr6-129505238-T-C is described in Lovd as [Benign]. Variant chr6-129505238-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.206 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.8586T>C	p.Tyr2862Tyr	synonymous_variant	Exon 61 of 65	ENST00000421865.3	NP_000417.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.8586T>C	p.Tyr2862Tyr	synonymous_variant	Exon 61 of 65	5	NM_000426.4	ENSP00000400365.2

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152180 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000736 AC: 185 AN: 251284 Hom.: 0 AF XY: 0.000722 AC XY: 98 AN XY: 135816

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000706 AC: 1032 AN: 1461650 Hom.: 2 Cov.: 30 AF XY: 0.000644 AC XY: 468 AN XY: 727172

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000556

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000753

Gnomad4 OTH exome AF: 0.000927

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.000725 AC XY: 54 AN XY: 74484

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000809

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000671 Hom.: 0

Bravo AF: 0.000952

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Dec 15, 2017

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LAMA2: BP4, BP7 -

Apr 19, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12552556) -

Congenital muscular dystrophy due to partial LAMA2 deficiency Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LAMA2-related muscular dystrophy Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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	-0.87
CADD	Benign	1.7
DANN	Benign	0.54

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: rs142451929; hg19: chr6-129826383; COSMIC: COSV70355278; COSMIC: COSV70355278;