rs35579821

chr6-129369966-C-Achr6-129369966-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_000426.4(LAMA2):c.4935C>A(p.Thr1645=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000681 in 1,613,884 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1645T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (3 hom.)
• Consequence: LAMA2 NM_000426.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0290

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 6-129369966-C-A is Benign according to our data. Variant chr6-129369966-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 256072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129369966-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.029 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00289 (439/152146) while in subpopulation AFR AF= 0.00976 (405/41512). AF 95% confidence interval is 0.00897. There are 1 homozygotes in gnomad4. There are 219 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.4935C>A	p.Thr1645=	synonymous_variant	34/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.4935C>A	p.Thr1645=	synonymous_variant	34/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.4935C>A	p.Thr1645=	synonymous_variant	34/65	5	NM_000426.4
LAMA2	ENST00000618192.5	c.5199C>A	p.Thr1733=	synonymous_variant	35/66	5		P1
LAMA2	ENST00000617695.5	c.4935C>A	p.Thr1645=	synonymous_variant	34/64	5
LAMA2	ENST00000687590.1	n.1355C>A		non_coding_transcript_exon_variant	2/5

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 439 AN: 152028 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00978

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.000889 AC: 223 AN: 250750 Hom.: 0 AF XY: 0.000709 AC XY: 96 AN XY: 135496

Gnomad AFR exome AF: 0.00905

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000452 AC: 660 AN: 1461738 Hom.: 3 Cov.: 31 AF XY: 0.000439 AC XY: 319 AN XY: 727170

Gnomad4 AFR exome AF: 0.0115

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000540

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00289 AC: 439 AN: 152146 Hom.: 1 Cov.: 32 AF XY: 0.00295 AC XY: 219 AN XY: 74362

Gnomad4 AFR AF: 0.00976

Gnomad4 AMR AF: 0.000982

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00157 Hom.: 1

Bravo AF: 0.00334

Asia WGS AF: 0.00181 AC: 6 AN: 3332

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 18, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 02, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	LAMA2: BP4, BP7 -

LAMA2-related muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Congenital muscular dystrophy due to partial LAMA2 deficiency Benign:1

Likely 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 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	-0.61
Cadd	Benign	0.43
Dann	Benign	0.66

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: rs35579821; hg19: chr6-129691111;