rs36044314

chr6-129250127-G-Achr6-129250127-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000426.4(LAMA2):c.1798G>A(p.Gly600Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0177 in 1,601,344 control chromosomes in the GnomAD database, including 329 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (29 hom., cov: 32)
  • Exomes 𝑓: 0.018 (300 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 6.08

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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, PROVEAN [when BayesDel_addAF, BayesDel_noAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.008395851).
• BP6: Variant 6-129250127-G-A is Benign according to our data. Variant chr6-129250127-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129250127-G-A is described in Lovd as [Benign]. Variant chr6-129250127-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0129 (1958/152228) while in subpopulation SAS AF= 0.02 (96/4810). AF 95% confidence interval is 0.0184. There are 29 homozygotes in gnomad4. There are 929 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.1798G>A	p.Gly600Arg	missense_variant	13/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.1798G>A	p.Gly600Arg	missense_variant	13/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.1798G>A	p.Gly600Arg	missense_variant	13/65	5	NM_000426.4
LAMA2	ENST00000618192.5	c.1798G>A	p.Gly600Arg	missense_variant	13/66	5		P1
LAMA2	ENST00000617695.5	c.1798G>A	p.Gly600Arg	missense_variant	13/64	5

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1956 AN: 152110 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0195

Gnomad FIN AF: 0.00998

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0193

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0139 AC: 3479 AN: 251146 Hom.: 28 AF XY: 0.0144 AC XY: 1960 AN XY: 135732

Gnomad AFR exome AF: 0.00363

Gnomad AMR exome AF: 0.00847

Gnomad ASJ exome AF: 0.0281

Gnomad EAS exome AF: 0.000708

Gnomad SAS exome AF: 0.0163

Gnomad FIN exome AF: 0.00873

Gnomad NFE exome AF: 0.0181

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.0182 AC: 26388 AN: 1449116 Hom.: 300 Cov.: 28 AF XY: 0.0184 AC XY: 13286 AN XY: 721918

Gnomad4 AFR exome AF: 0.00338

Gnomad4 AMR exome AF: 0.00879

Gnomad4 ASJ exome AF: 0.0254

Gnomad4 EAS exome AF: 0.000682

Gnomad4 SAS exome AF: 0.0158

Gnomad4 FIN exome AF: 0.00825

Gnomad4 NFE exome AF: 0.0202

Gnomad4 OTH exome AF: 0.0167

GnomAD4 genome AF: 0.0129 AC: 1958 AN: 152228 Hom.: 29 Cov.: 32 AF XY: 0.0125 AC XY: 929 AN XY: 74430

Gnomad4 AFR AF: 0.00303

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.0233

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0200

Gnomad4 FIN AF: 0.00998

Gnomad4 NFE AF: 0.0193

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0188 Hom.: 50

Bravo AF: 0.0124

TwinsUK AF: 0.0165 AC: 61

ALSPAC AF: 0.0187 AC: 72

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0206 AC: 177

ExAC AF: 0.0132 AC: 1604

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.0212

EpiControl AF: 0.0187

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 19, 2015	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	LAMA2: BS1, BS2 -

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

Jan 13, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D;D;D
MetaRNN	Benign	0.0084	T;T;T
MetaSVM	Benign	-0.68	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
Polyphen		1.0	.;.;D
Vest4		0.68
MutPred		0.93		Loss of catalytic residue at P596 (P = 0.0966);Loss of catalytic residue at P596 (P = 0.0966);Loss of catalytic residue at P596 (P = 0.0966);
MPC		0.51
ClinPred		0.029	T
GERP RS		5.7
Varity_R		0.89
gMVP		0.89

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: rs36044314; hg19: chr6-129571272;