rs35089085

Variant names:

• chr6-129349331-C-T
• rs35089085
• NM_000426.4:c.4470C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000426.4(LAMA2):​c.4470C>T​(p.Asp1490Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00819 in 1,613,168 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (73 hom.)
• Consequence: LAMA2 NM_000426.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.00

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=-0.43).
• BP6: Variant 6-129349331-C-T is Benign according to our data. Variant chr6-129349331-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 92959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129349331-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00532 (810/152162) while in subpopulation NFE AF= 0.00847 (576/68014). AF 95% confidence interval is 0.0079. There are 4 homozygotes in gnomad4. There are 364 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.4470C>T	p.Asp1490Asp	synonymous_variant	Exon 31 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.4470C>T	p.Asp1490Asp	synonymous_variant	Exon 31 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.4470C>T	p.Asp1490Asp	synonymous_variant	Exon 31 of 65	5	NM_000426.4	ENSP00000400365.2

Frequencies

GnomAD3 genomes AF: 0.00534 AC: 812 AN: 152044 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00322

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00847

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00557 AC: 1400 AN: 251380 Hom.: 4 AF XY: 0.00572 AC XY: 777 AN XY: 135860

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00199

Gnomad FIN exome AF: 0.00291

Gnomad NFE exome AF: 0.00819

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00849 AC: 12398 AN: 1461006 Hom.: 73 Cov.: 30 AF XY: 0.00817 AC XY: 5941 AN XY: 726822

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00338

Gnomad4 ASJ exome AF: 0.0147

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00199

Gnomad4 FIN exome AF: 0.00309

Gnomad4 NFE exome AF: 0.00966

Gnomad4 OTH exome AF: 0.0115

GnomAD4 genome AF: 0.00532 AC: 810 AN: 152162 Hom.: 4 Cov.: 32 AF XY: 0.00489 AC XY: 364 AN XY: 74398

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.00321

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00255

Gnomad4 NFE AF: 0.00847

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00820 Hom.: 3

Bravo AF: 0.00530

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00927

EpiControl AF: 0.00848

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Dec 08, 2017

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. -

Apr 17, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LAMA2: BP4, BP7, BS1, BS2 -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

LAMA2-related muscular dystrophy Benign:1

Jan 25, 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: Likely 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 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
BayesDel_noAF	Benign	-0.43
CADD	Benign	3.8
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35089085; hg19: chr6-129670476; COSMIC: COSV104710941;