rs3828735

Positions:

• chr6-129403797-T-A
• chr6-129403797-T-C
• chr6-129403797-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000426.4(LAMA2):​c.5727-24T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 1,594,536 control chromosomes in the GnomAD database, including 176,592 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19480 hom., cov: 32)
  • Exomes 𝑓: 0.46 (157112 hom.)
• Consequence: LAMA2 NM_000426.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.28

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 6-129403797-T-A is Benign according to our data. Variant chr6-129403797-T-A is described in ClinVar as [Benign]. Clinvar id is 256076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129403797-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.5727-24T>A		intron_variant		ENST00000421865.3
LAMA2	NM_001079823.2	c.5727-24T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.5727-24T>A		intron_variant		5	NM_000426.4
LAMA2	ENST00000617695.5	c.5727-24T>A		intron_variant		5
LAMA2	ENST00000618192.5	c.5991-24T>A		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.501 AC: 75842 AN: 151470 Hom.: 19436 Cov.: 32

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.546

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.474

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.493

GnomAD3 exomes AF: 0.485 AC: 121078 AN: 249442 Hom.: 29699 AF XY: 0.485 AC XY: 65385 AN XY: 134938

Gnomad AFR exome AF: 0.619

Gnomad AMR exome AF: 0.467

Gnomad ASJ exome AF: 0.527

Gnomad EAS exome AF: 0.567

Gnomad SAS exome AF: 0.536

Gnomad FIN exome AF: 0.445

Gnomad NFE exome AF: 0.449

Gnomad OTH exome AF: 0.472

GnomAD4 exome AF: 0.462 AC: 667086 AN: 1442946 Hom.: 157112 Cov.: 32 AF XY: 0.464 AC XY: 333496 AN XY: 718816

Gnomad4 AFR exome AF: 0.630

Gnomad4 AMR exome AF: 0.473

Gnomad4 ASJ exome AF: 0.530

Gnomad4 EAS exome AF: 0.531

Gnomad4 SAS exome AF: 0.539

Gnomad4 FIN exome AF: 0.457

Gnomad4 NFE exome AF: 0.446

Gnomad4 OTH exome AF: 0.473

GnomAD4 genome AF: 0.501 AC: 75955 AN: 151590 Hom.: 19480 Cov.: 32 AF XY: 0.501 AC XY: 37119 AN XY: 74036

Gnomad4 AFR AF: 0.616

Gnomad4 AMR AF: 0.458

Gnomad4 ASJ AF: 0.512

Gnomad4 EAS AF: 0.547

Gnomad4 SAS AF: 0.529

Gnomad4 FIN AF: 0.438

Gnomad4 NFE AF: 0.445

Gnomad4 OTH AF: 0.491

Alfa AF: 0.395 Hom.: 1773

Bravo AF: 0.509

Asia WGS AF: 0.510 AC: 1775 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Merosin deficient congenital muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2018

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. -

Muscular dystrophy, limb-girdle, autosomal recessive 23 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.5
DANN	Benign	0.74

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: rs3828735; hg19: chr6-129724942; COSMIC: COSV70353211;