rs2244008

chr6-129491908-A-G

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.7906A>G(p.Thr2636Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0722 in 1,605,722 control chromosomes in the GnomAD database, including 4,812 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2636T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.087 (631 hom., cov: 32)
  • Exomes 𝑓: 0.071 (4181 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.99

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=0.0020777285).
• BP6: Variant 6-129491908-A-G is Benign according to our data. Variant chr6-129491908-A-G is described in ClinVar as [Benign]. Clinvar id is 92989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129491908-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.7906A>G	p.Thr2636Ala	missense_variant	57/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.7894A>G	p.Thr2632Ala	missense_variant	56/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.7906A>G	p.Thr2636Ala	missense_variant	57/65	5	NM_000426.4
	ENST00000665046.1	n.975+10697T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0875 AC: 13305 AN: 152096 Hom.: 634 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0737

Gnomad ASJ AF: 0.0833

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0638

Gnomad OTH AF: 0.0824

GnomAD3 exomes AF: 0.0872 AC: 21834 AN: 250466 Hom.: 1124 AF XY: 0.0862 AC XY: 11673 AN XY: 135430

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.0733

Gnomad ASJ exome AF: 0.0855

Gnomad EAS exome AF: 0.182

Gnomad SAS exome AF: 0.0912

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.0672

Gnomad OTH exome AF: 0.0751

GnomAD4 exome AF: 0.0706 AC: 102602 AN: 1453508 Hom.: 4181 Cov.: 31 AF XY: 0.0711 AC XY: 51460 AN XY: 723670

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.0704

Gnomad4 ASJ exome AF: 0.0855

Gnomad4 EAS exome AF: 0.163

Gnomad4 SAS exome AF: 0.0890

Gnomad4 FIN exome AF: 0.114

Gnomad4 NFE exome AF: 0.0619

Gnomad4 OTH exome AF: 0.0783

GnomAD4 genome AF: 0.0874 AC: 13302 AN: 152214 Hom.: 631 Cov.: 32 AF XY: 0.0906 AC XY: 6745 AN XY: 74420

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.0737

Gnomad4 ASJ AF: 0.0833

Gnomad4 EAS AF: 0.164

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.0638

Gnomad4 OTH AF: 0.0815

Alfa AF: 0.0714 Hom.: 1053

Bravo AF: 0.0867

TwinsUK AF: 0.0647 AC: 240

ALSPAC AF: 0.0602 AC: 232

ESP6500AA AF: 0.116 AC: 509

ESP6500EA AF: 0.0630 AC: 542

ExAC AF: 0.0879 AC: 10668

Asia WGS AF: 0.119 AC: 412 AN: 3478

EpiCase AF: 0.0632

EpiControl AF: 0.0636

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 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. -

Merosin deficient congenital muscular dystrophy Benign:1

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

Invitae

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	0.075
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.0057
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.78	T;T;T
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	0.18	P
PrimateAI	Benign	0.41	T
Polyphen		0.015	.;.;B
Vest4		0.082
MPC		0.088
ClinPred		0.035	T
GERP RS		5.5
Varity_R		0.16
gMVP		0.45

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: rs2244008; hg19: chr6-129813053; COSMIC: COSV70340957;