rs141190803

chr6-129445671-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_000426.4(LAMA2):c.6279C>T(p.Ala2093=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00067 in 1,613,644 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (0 hom.)
• Consequence: LAMA2 NM_000426.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.01

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 6-129445671-C-T is Benign according to our data. Variant chr6-129445671-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 477499.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}. Variant chr6-129445671-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.01 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00164 (250/152222) while in subpopulation AFR AF= 0.00441 (183/41520). AF 95% confidence interval is 0.00389. There are 0 homozygotes in gnomad4. There are 112 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.6279C>T	p.Ala2093=	synonymous_variant	45/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.6279C>T	p.Ala2093=	synonymous_variant	45/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.6279C>T	p.Ala2093=	synonymous_variant	45/65	5	NM_000426.4
	ENST00000665046.1	n.976-4419G>A		intron_variant, non_coding_transcript_variant
LAMA2	ENST00000618192.5	c.6543C>T	p.Ala2181=	synonymous_variant	46/66	5		P1
LAMA2	ENST00000617695.5	c.6279C>T	p.Ala2093=	synonymous_variant	45/64	5

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 249 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00440

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000834 AC: 209 AN: 250598 Hom.: 0 AF XY: 0.000783 AC XY: 106 AN XY: 135446

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000929

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000569 AC: 831 AN: 1461422 Hom.: 0 Cov.: 31 AF XY: 0.000541 AC XY: 393 AN XY: 727024

Gnomad4 AFR exome AF: 0.00514

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.000766

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000512

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.00150 AC XY: 112 AN XY: 74430

Gnomad4 AFR AF: 0.00441

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00204

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2021	This variant is associated with the following publications: (PMID: 21896784) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	LAMA2: BP4, BP7 -

Congenital muscular dystrophy due to partial LAMA2 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

LAMA2-related muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

LAMA2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
Cadd	Benign	13
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs141190803; hg19: chr6-129766816;