rs2229848

chr6-129486484-C-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.7760C>T(p.Ala2587Val) variant causes a missense change. The variant allele was found at a frequency of 0.695 in 1,612,146 control chromosomes in the GnomAD database, including 393,345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (31327 hom., cov: 32)
  • Exomes 𝑓: 0.70 (362018 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.63

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 (MetaRNN=1.0597179E-5).
• BP6: Variant 6-129486484-C-T is Benign according to our data. Variant chr6-129486484-C-T is described in ClinVar as [Benign]. Clinvar id is 167247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129486484-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.7760C>T	p.Ala2587Val	missense_variant	56/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.7748C>T	p.Ala2583Val	missense_variant	55/64
LOC124901401	XR_007059767.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.7760C>T	p.Ala2587Val	missense_variant	56/65	5	NM_000426.4
	ENST00000665046.1	n.975+16121G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.632 AC: 95962 AN: 151854 Hom.: 31302 Cov.: 32

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.830

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.616

Gnomad FIN AF: 0.657

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.720

Gnomad OTH AF: 0.654

GnomAD3 exomes AF: 0.672 AC: 168513 AN: 250778 Hom.: 57254 AF XY: 0.677 AC XY: 91681 AN XY: 135520

Gnomad AFR exome AF: 0.448

Gnomad AMR exome AF: 0.677

Gnomad ASJ exome AF: 0.750

Gnomad EAS exome AF: 0.605

Gnomad SAS exome AF: 0.649

Gnomad FIN exome AF: 0.646

Gnomad NFE exome AF: 0.717

Gnomad OTH exome AF: 0.684

GnomAD4 exome AF: 0.702 AC: 1024939 AN: 1460174 Hom.: 362018 Cov.: 43 AF XY: 0.701 AC XY: 509109 AN XY: 726458

Gnomad4 AFR exome AF: 0.446

Gnomad4 AMR exome AF: 0.679

Gnomad4 ASJ exome AF: 0.750

Gnomad4 EAS exome AF: 0.628

Gnomad4 SAS exome AF: 0.650

Gnomad4 FIN exome AF: 0.641

Gnomad4 NFE exome AF: 0.720

Gnomad4 OTH exome AF: 0.685

GnomAD4 genome AF: 0.632 AC: 96029 AN: 151972 Hom.: 31327 Cov.: 32 AF XY: 0.630 AC XY: 46794 AN XY: 74256

Gnomad4 AFR AF: 0.454

Gnomad4 AMR AF: 0.670

Gnomad4 ASJ AF: 0.737

Gnomad4 EAS AF: 0.629

Gnomad4 SAS AF: 0.618

Gnomad4 FIN AF: 0.657

Gnomad4 NFE AF: 0.720

Gnomad4 OTH AF: 0.658

Alfa AF: 0.705 Hom.: 77392

Bravo AF: 0.625

TwinsUK AF: 0.714 AC: 2648

ALSPAC AF: 0.724 AC: 2791

ESP6500AA AF: 0.467 AC: 2058

ESP6500EA AF: 0.727 AC: 6248

ExAC AF: 0.667 AC: 81020

Asia WGS AF: 0.635 AC: 2208 AN: 3478

EpiCase AF: 0.725

EpiControl AF: 0.727

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

Merosin deficient congenital muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

LAMA2-related muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D
MetaRNN	Benign	0.000011	T;T;T
MetaSVM	Uncertain	0.056	D
MutationTaster	Benign	7.1e-7	P
PrimateAI	Uncertain	0.66	T
Polyphen		1.0	.;.;D
Vest4		0.58
MPC		0.45
ClinPred		0.017	T
GERP RS		5.6
Varity_R		0.28
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2229848; hg19: chr6-129807629; COSMIC: COSV70342789; COSMIC: COSV70342789;