chr6-129300910-A-G

Position:

• chr6-129300910-A-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.3174+38A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.416 in 1,608,002 control chromosomes in the GnomAD database, including 144,614 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (10583 hom., cov: 32)
  • Exomes 𝑓: 0.42 (134031 hom.)
• Consequence: LAMA2 NM_000426.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.300

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=-0.85).
• BP6: Variant 6-129300910-A-G is Benign according to our data. Variant chr6-129300910-A-G is described in ClinVar as [Benign]. Clinvar id is 256064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129300910-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.3174+38A>G		intron_variant		ENST00000421865.3
LAMA2	NM_001079823.2	c.3174+38A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.3174+38A>G		intron_variant		5	NM_000426.4
LAMA2	ENST00000617695.5	c.3174+38A>G		intron_variant		5
LAMA2	ENST00000618192.5	c.3438+38A>G		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52307 AN: 151882 Hom.: 10587 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.544

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.449

Gnomad OTH AF: 0.384

GnomAD3 exomes AF: 0.396 AC: 99290 AN: 250836 Hom.: 21054 AF XY: 0.406 AC XY: 55099 AN XY: 135632

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.294

Gnomad ASJ exome AF: 0.563

Gnomad EAS exome AF: 0.293

Gnomad SAS exome AF: 0.436

Gnomad FIN exome AF: 0.377

Gnomad NFE exome AF: 0.456

Gnomad OTH exome AF: 0.424

GnomAD4 exome AF: 0.423 AC: 615939 AN: 1456002 Hom.: 134031 Cov.: 31 AF XY: 0.426 AC XY: 308633 AN XY: 724740

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.302

Gnomad4 ASJ exome AF: 0.559

Gnomad4 EAS exome AF: 0.277

Gnomad4 SAS exome AF: 0.438

Gnomad4 FIN exome AF: 0.384

Gnomad4 NFE exome AF: 0.440

Gnomad4 OTH exome AF: 0.409

GnomAD4 genome AF: 0.344 AC: 52314 AN: 152000 Hom.: 10583 Cov.: 32 AF XY: 0.342 AC XY: 25426 AN XY: 74290

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.327

Gnomad4 ASJ AF: 0.572

Gnomad4 EAS AF: 0.283

Gnomad4 SAS AF: 0.415

Gnomad4 FIN AF: 0.383

Gnomad4 NFE AF: 0.449

Gnomad4 OTH AF: 0.385

Alfa AF: 0.428 Hom.: 3837

Bravo AF: 0.331

Asia WGS AF: 0.403 AC: 1400 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 19, 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	-0.85
CADD	Benign	0.28
DANN	Benign	0.71

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: rs902373; hg19: chr6-129622055; COSMIC: COSV70342530; COSMIC: COSV70342530;