rs146462599

chr6-129148991-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000426.4(LAMA2):c.922G>A(p.Glu308Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00119 in 1,612,440 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:3
• Conservation: PhyloP100: 6.29

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1259566).
• BP6: Variant 6-129148991-G-A is Benign according to our data. Variant chr6-129148991-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235618.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.922G>A	p.Glu308Lys	missense_variant	7/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.922G>A	p.Glu308Lys	missense_variant	7/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.922G>A	p.Glu308Lys	missense_variant	7/65	5	NM_000426.4

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00106 AC: 267 AN: 251330 Hom.: 0 AF XY: 0.00120 AC XY: 163 AN XY: 135826

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00180

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00122 AC: 1785 AN: 1460224 Hom.: 4 Cov.: 30 AF XY: 0.00130 AC XY: 944 AN XY: 726540

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00182

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00131

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.000913 AC: 139 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000887 AC XY: 66 AN XY: 74426

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00145 Hom.: 1

Bravo AF: 0.00100

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00114 AC: 138

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 22, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 29, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	LAMA2: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 05, 2023	BP4 -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 05, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 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. -

Congenital muscular dystrophy due to partial LAMA2 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

LAMA2-related muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
Polyphen		0.95	.;.;P
Vest4		0.59
MVP		0.79
MPC		0.44
ClinPred		0.033	T
GERP RS		5.9
Varity_R		0.27
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146462599; hg19: chr6-129470136;