6-129464246-T-C

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.6993-44T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 1,545,330 control chromosomes in the GnomAD database, including 279,127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32749 hom., cov: 31)
  • Exomes 𝑓: 0.59 (246378 hom.)
• Consequence: LAMA2 NM_000426.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.72

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-129464246-T-C is Benign according to our data. Variant chr6-129464246-T-C is described in ClinVar as [Benign]. Clinvar id is 256084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129464246-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.6993-44T>C		intron_variant		ENST00000421865.3
LAMA2	NM_001079823.2	c.6993-44T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.6993-44T>C		intron_variant		5	NM_000426.4
	ENST00000665046.1	n.976-22994A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98143 AN: 151622 Hom.: 32701 Cov.: 31

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.703

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.540

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.549

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.629

GnomAD3 exomes AF: 0.610 AC: 152214 AN: 249648 Hom.: 47133 AF XY: 0.605 AC XY: 81609 AN XY: 134944

Gnomad AFR exome AF: 0.825

Gnomad AMR exome AF: 0.648

Gnomad ASJ exome AF: 0.624

Gnomad EAS exome AF: 0.553

Gnomad SAS exome AF: 0.634

Gnomad FIN exome AF: 0.562

Gnomad NFE exome AF: 0.578

Gnomad OTH exome AF: 0.594

GnomAD4 exome AF: 0.592 AC: 825441 AN: 1393590 Hom.: 246378 Cov.: 23 AF XY: 0.592 AC XY: 412991 AN XY: 697274

Gnomad4 AFR exome AF: 0.831

Gnomad4 AMR exome AF: 0.650

Gnomad4 ASJ exome AF: 0.625

Gnomad4 EAS exome AF: 0.537

Gnomad4 SAS exome AF: 0.636

Gnomad4 FIN exome AF: 0.568

Gnomad4 NFE exome AF: 0.581

Gnomad4 OTH exome AF: 0.598

GnomAD4 genome AF: 0.648 AC: 98257 AN: 151740 Hom.: 32749 Cov.: 31 AF XY: 0.645 AC XY: 47861 AN XY: 74152

Gnomad4 AFR AF: 0.815

Gnomad4 AMR AF: 0.624

Gnomad4 ASJ AF: 0.615

Gnomad4 EAS AF: 0.541

Gnomad4 SAS AF: 0.623

Gnomad4 FIN AF: 0.549

Gnomad4 NFE AF: 0.577

Gnomad4 OTH AF: 0.625

Alfa AF: 0.590 Hom.: 40539

Bravo AF: 0.661

Asia WGS AF: 0.573 AC: 1992 AN: 3476

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	-0.90
Cadd	Benign	0.36
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: rs1414736; hg19: chr6-129785391;