rs7754560

Positions:

• chr6-129143875-G-A
• chr6-129143875-G-T

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.640-26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,502,734 control chromosomes in the GnomAD database, including 33,958 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5257 hom., cov: 32)
  • Exomes 𝑓: 0.20 (28701 hom.)
• Consequence: LAMA2 NM_000426.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.303

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=-0.82).
• BP6: Variant 6-129143875-G-A is Benign according to our data. Variant chr6-129143875-G-A is described in ClinVar as [Benign]. Clinvar id is 256079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129143875-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) 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.640-26G>A		intron_variant		ENST00000421865.3
LAMA2	NM_001079823.2	c.640-26G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.640-26G>A		intron_variant		5	NM_000426.4

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37442 AN: 151730 Hom.: 5257 Cov.: 32

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.229

GnomAD3 exomes AF: 0.193 AC: 45623 AN: 236086 Hom.: 4790 AF XY: 0.196 AC XY: 25072 AN XY: 127618

Gnomad AFR exome AF: 0.380

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.130

Gnomad SAS exome AF: 0.239

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.189

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.202 AC: 272252 AN: 1350886 Hom.: 28701 Cov.: 20 AF XY: 0.203 AC XY: 137054 AN XY: 676704

Gnomad4 AFR exome AF: 0.384

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.182

Gnomad4 EAS exome AF: 0.143

Gnomad4 SAS exome AF: 0.240

Gnomad4 FIN exome AF: 0.202

Gnomad4 NFE exome AF: 0.198

Gnomad4 OTH exome AF: 0.209

GnomAD4 genome AF: 0.247 AC: 37480 AN: 151848 Hom.: 5257 Cov.: 32 AF XY: 0.244 AC XY: 18108 AN XY: 74222

Gnomad4 AFR AF: 0.391

Gnomad4 AMR AF: 0.170

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.140

Gnomad4 SAS AF: 0.247

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.197

Gnomad4 OTH AF: 0.232

Alfa AF: 0.205 Hom.: 651

Bravo AF: 0.249

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

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 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	-0.82
CADD	Benign	4.6
DANN	Benign	0.61

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: rs7754560; hg19: chr6-129465020; COSMIC: COSV70355579;