rs11967042

Positions:

• chr6-129297914-G-A

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.3037+49G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,504,734 control chromosomes in the GnomAD database, including 11,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1433 hom., cov: 33)
  • Exomes 𝑓: 0.10 (9632 hom.)
• Consequence: LAMA2 NM_000426.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.36

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=-0.92).
• BP6: Variant 6-129297914-G-A is Benign according to our data. Variant chr6-129297914-G-A is described in ClinVar as [Benign]. Clinvar id is 256063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129297914-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.3037+49G>A		intron_variant		ENST00000421865.3
LAMA2	NM_001079823.2	c.3037+49G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.3037+49G>A		intron_variant		5	NM_000426.4
LAMA2	ENST00000617695.5	c.3037+49G>A		intron_variant		5
LAMA2	ENST00000618192.5	c.3301+49G>A		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17728 AN: 151976 Hom.: 1430 Cov.: 33

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.0972

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0791

Gnomad OTH AF: 0.120

GnomAD3 exomes AF: 0.143 AC: 30729 AN: 214394 Hom.: 3194 AF XY: 0.135 AC XY: 15562 AN XY: 114978

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.277

Gnomad ASJ exome AF: 0.0966

Gnomad EAS exome AF: 0.390

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.0800

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.102 AC: 137753 AN: 1352640 Hom.: 9632 Cov.: 20 AF XY: 0.101 AC XY: 68130 AN XY: 676048

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.267

Gnomad4 ASJ exome AF: 0.0990

Gnomad4 EAS exome AF: 0.386

Gnomad4 SAS exome AF: 0.101

Gnomad4 FIN exome AF: 0.133

Gnomad4 NFE exome AF: 0.0816

Gnomad4 OTH exome AF: 0.115

GnomAD4 genome AF: 0.117 AC: 17749 AN: 152094 Hom.: 1433 Cov.: 33 AF XY: 0.123 AC XY: 9121 AN XY: 74350

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.202

Gnomad4 ASJ AF: 0.0972

Gnomad4 EAS AF: 0.401

Gnomad4 SAS AF: 0.111

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.0791

Gnomad4 OTH AF: 0.119

Alfa AF: 0.102 Hom.: 304

Bravo AF: 0.126

Asia WGS AF: 0.202 AC: 706 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

-

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.093
DANN	Benign	0.44

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: rs11967042; hg19: chr6-129619059;