rs35313209

Positions:

• chr6-129492030-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000426.4(LAMA2):​c.8028T>C​(p.Asn2676=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,614,016 control chromosomes in the GnomAD database, including 260 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (63 hom., cov: 32)
  • Exomes 𝑓: 0.014 (197 hom.)
• Consequence: LAMA2 NM_000426.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.466

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 6-129492030-T-C is Benign according to our data. Variant chr6-129492030-T-C is described in ClinVar as [Benign]. Clinvar id is 129443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129492030-T-C is described in Lovd as [Benign]. Variant chr6-129492030-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.466 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0216 (3291/152274) while in subpopulation AFR AF= 0.0485 (2016/41530). AF 95% confidence interval is 0.0468. There are 63 homozygotes in gnomad4. There are 1517 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 63 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.8028T>C	p.Asn2676=	synonymous_variant	57/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.8016T>C	p.Asn2672=	synonymous_variant	56/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.8028T>C	p.Asn2676=	synonymous_variant	57/65	5	NM_000426.4	ENSP00000400365
	ENST00000665046.1	n.975+10575A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3265 AN: 152156 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.0480

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.0230

GnomAD3 exomes AF: 0.0122 AC: 3056 AN: 251250 Hom.: 35 AF XY: 0.0113 AC XY: 1528 AN XY: 135788

Gnomad AFR exome AF: 0.0501

Gnomad AMR exome AF: 0.00688

Gnomad ASJ exome AF: 0.00834

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00245

Gnomad FIN exome AF: 0.00559

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0137 AC: 20018 AN: 1461742 Hom.: 197 Cov.: 32 AF XY: 0.0135 AC XY: 9781 AN XY: 727182

Gnomad4 AFR exome AF: 0.0516

Gnomad4 AMR exome AF: 0.00830

Gnomad4 ASJ exome AF: 0.00685

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00245

Gnomad4 FIN exome AF: 0.00672

Gnomad4 NFE exome AF: 0.0145

Gnomad4 OTH exome AF: 0.0161

GnomAD4 genome AF: 0.0216 AC: 3291 AN: 152274 Hom.: 63 Cov.: 32 AF XY: 0.0204 AC XY: 1517 AN XY: 74478

Gnomad4 AFR AF: 0.0485

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0174 Hom.: 15

Bravo AF: 0.0234

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0125

EpiControl AF: 0.0116

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	GeneDx	Feb 29, 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:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 27, 2017

- -

LAMA2-related muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

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

-

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.7
DANN	Benign	0.72

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: rs35313209; hg19: chr6-129813175;