rs3816665

Positions:

• chr6-129250185-G-A

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.1856G>A​(p.Arg619His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,595,278 control chromosomes in the GnomAD database, including 27,206 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (7179 hom., cov: 32)
  • Exomes 𝑓: 0.15 (20027 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.57

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=3.9240298E-5).
• BP6: Variant 6-129250185-G-A is Benign according to our data. Variant chr6-129250185-G-A is described in ClinVar as [Benign]. Clinvar id is 92943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129250185-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.1856G>A	p.Arg619His	missense_variant	13/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.1856G>A	p.Arg619His	missense_variant	13/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.1856G>A	p.Arg619His	missense_variant	13/65	5	NM_000426.4	ENSP00000400365
LAMA2	ENST00000618192.5	c.1856G>A	p.Arg619His	missense_variant	13/66	5		ENSP00000480802	P1
LAMA2	ENST00000617695.5	c.1856G>A	p.Arg619His	missense_variant	13/64	5		ENSP00000481744

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37925 AN: 151884 Hom.: 7155 Cov.: 32

Gnomad AFR AF: 0.533

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.0903

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.211

GnomAD3 exomes AF: 0.174 AC: 43614 AN: 251036 Hom.: 5258 AF XY: 0.172 AC XY: 23310 AN XY: 135702

Gnomad AFR exome AF: 0.542

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.0785

Gnomad SAS exome AF: 0.234

Gnomad FIN exome AF: 0.190

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.151 AC: 217711 AN: 1443276 Hom.: 20027 Cov.: 28 AF XY: 0.153 AC XY: 109798 AN XY: 719284

Gnomad4 AFR exome AF: 0.547

Gnomad4 AMR exome AF: 0.122

Gnomad4 ASJ exome AF: 0.157

Gnomad4 EAS exome AF: 0.0952

Gnomad4 SAS exome AF: 0.232

Gnomad4 FIN exome AF: 0.184

Gnomad4 NFE exome AF: 0.133

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.250 AC: 37996 AN: 152002 Hom.: 7179 Cov.: 32 AF XY: 0.249 AC XY: 18520 AN XY: 74298

Gnomad4 AFR AF: 0.533

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.153

Gnomad4 EAS AF: 0.0899

Gnomad4 SAS AF: 0.228

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.211

Alfa AF: 0.154 Hom.: 5506

Bravo AF: 0.257

TwinsUK AF: 0.136 AC: 506

ALSPAC AF: 0.132 AC: 508

ESP6500AA AF: 0.523 AC: 2304

ESP6500EA AF: 0.140 AC: 1204

ExAC AF: 0.183 AC: 22176

Asia WGS AF: 0.200 AC: 697 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Merosin deficient congenital muscular dystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 13, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

LAMA2-related muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Congenital muscular dystrophy due to partial LAMA2 deficiency Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.0070
DANN	Benign	0.73
DEOGEN2	Benign	0.015	.;T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.38	T;T;T
MetaRNN	Benign	0.000039	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;.;L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.050	.;.;N
REVEL	Benign	0.063
Sift	Benign	0.29	.;.;T
Polyphen		0.0	.;.;B
Vest4		0.030
MPC		0.11
ClinPred		0.0018	T
GERP RS		-5.1
Varity_R		0.022
gMVP		0.34

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: rs3816665; hg19: chr6-129571330; COSMIC: COSV70358074;