NM_000426.4:c.5558T>G

Variant names:

• chr6-129401336-T-G
• rs141911213
• NM_000426.4:c.5558T>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000426.4(LAMA2):​c.5558T>G​(p.Ile1853Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,556,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 2.88

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041600555).
• BP6: Variant 6-129401336-T-G is Benign according to our data. Variant chr6-129401336-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 355280.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.5558T>G	p.Ile1853Arg	missense_variant	Exon 38 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.5558T>G	p.Ile1853Arg	missense_variant	Exon 38 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.5558T>G	p.Ile1853Arg	missense_variant	Exon 38 of 65	5	NM_000426.4	ENSP00000400365.2
LAMA2	ENST00000618192.5	c.5822T>G	p.Ile1941Arg	missense_variant	Exon 39 of 66	5		ENSP00000480802.2
LAMA2	ENST00000617695.5	c.5558T>G	p.Ile1853Arg	missense_variant	Exon 38 of 64	5		ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000236 AC: 59 AN: 250326 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135306

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000165 AC: 232 AN: 1403852 Hom.: 0 Cov.: 24 AF XY: 0.000167 AC XY: 117 AN XY: 701966

Gnomad4 AFR exome AF: 0.0000624

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00237

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000126

Gnomad4 OTH exome AF: 0.000325

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74476

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000368 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Oct 04, 2023

Revvity Omics, Revvity

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 21, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 19, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital muscular dystrophy due to partial LAMA2 deficiency Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LAMA2-related disorder Benign:1

Sep 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.057	.;T;T
Eigen	Benign	-0.018
Eigen_PC	Benign	0.042
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	.;.;M
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.0	.;.;N
REVEL	Benign	0.12
Sift	Uncertain	0.018	.;.;D
Polyphen		0.71	.;.;P
Vest4		0.53
MVP		0.49
MPC		0.23
ClinPred		0.080	T
GERP RS		5.4
Varity_R		0.22
gMVP		0.51

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: rs141911213; hg19: chr6-129722481;