rs117781224

chr6-129366251-G-Achr6-129366251-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000426.4(LAMA2):c.4750G>A(p.Gly1584Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,613,708 control chromosomes in the GnomAD database, including 802 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (43 hom., cov: 31)
  • Exomes 𝑓: 0.029 (759 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.15

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 (MetaRNN=0.008308321).
• BP6: Variant 6-129366251-G-A is Benign according to our data. Variant chr6-129366251-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129366251-G-A is described in Lovd as [Pathogenic]. Variant chr6-129366251-G-A is described in Lovd as [Likely_benign]. Variant chr6-129366251-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0191 (2908/151944) while in subpopulation NFE AF= 0.0306 (2081/67942). AF 95% confidence interval is 0.0295. There are 43 homozygotes in gnomad4. There are 1368 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 44 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.4750G>A	p.Gly1584Ser	missense_variant	33/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.4750G>A	p.Gly1584Ser	missense_variant	33/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.4750G>A	p.Gly1584Ser	missense_variant	33/65	5	NM_000426.4

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2907 AN: 151826 Hom.: 44 Cov.: 31

Gnomad AFR AF: 0.00631

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00984

Gnomad FIN AF: 0.00824

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0306

Gnomad OTH AF: 0.0202

GnomAD3 exomes AF: 0.0195 AC: 4888 AN: 251002 Hom.: 75 AF XY: 0.0199 AC XY: 2701 AN XY: 135632

Gnomad AFR exome AF: 0.00578

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.0230

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0123

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.0302

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0295 AC: 43091 AN: 1461764 Hom.: 759 Cov.: 32 AF XY: 0.0288 AC XY: 20937 AN XY: 727200

Gnomad4 AFR exome AF: 0.00499

Gnomad4 AMR exome AF: 0.0119

Gnomad4 ASJ exome AF: 0.0205

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0122

Gnomad4 FIN exome AF: 0.0126

Gnomad4 NFE exome AF: 0.0345

Gnomad4 OTH exome AF: 0.0265

GnomAD4 genome AF: 0.0191 AC: 2908 AN: 151944 Hom.: 43 Cov.: 31 AF XY: 0.0184 AC XY: 1368 AN XY: 74258

Gnomad4 AFR AF: 0.00629

Gnomad4 AMR AF: 0.0206

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0101

Gnomad4 FIN AF: 0.00824

Gnomad4 NFE AF: 0.0306

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0279 Hom.: 124

Bravo AF: 0.0193

TwinsUK AF: 0.0337 AC: 125

ALSPAC AF: 0.0330 AC: 127

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.0330 AC: 284

ExAC AF: 0.0196 AC: 2382

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2016	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. -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	LAMA2: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

LAMA2-related muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Congenital muscular dystrophy due to partial LAMA2 deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	12
Dann	Uncertain	0.98
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.62	T;T;T
MetaRNN	Benign	0.0083	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.93	N
PrimateAI	Benign	0.34	T
Polyphen		0.013	.;.;B
Vest4		0.19
MPC		0.088
ClinPred		0.0081	T
GERP RS		3.5
Varity_R		0.038
gMVP		0.73

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: rs117781224; hg19: chr6-129687396;