chr6-129383155-G-A

Variant names:

• chr6-129383155-G-A
• rs373997222
• NM_000426.4:c.4993G>A

Variant summary

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

The NM_000426.4(LAMA2):​c.4993G>A​(p.Gly1665Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000335 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G1665G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 4.06

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=0.016704291).
• BP6: Variant 6-129383155-G-A is Benign according to our data. Variant chr6-129383155-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 355274.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}. Variant chr6-129383155-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.4993G>A	p.Gly1665Arg	missense_variant	Exon 35 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.4993G>A	p.Gly1665Arg	missense_variant	Exon 35 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.4993G>A	p.Gly1665Arg	missense_variant	Exon 35 of 65	5	NM_000426.4	ENSP00000400365.2
LAMA2	ENST00000618192.5	c.5257G>A	p.Gly1753Arg	missense_variant	Exon 36 of 66	5		ENSP00000480802.2
LAMA2	ENST00000617695.5	c.4993G>A	p.Gly1665Arg	missense_variant	Exon 35 of 64	5		ENSP00000481744.2
LAMA2	ENST00000687590.1	n.1413G>A		non_coding_transcript_exon_variant	Exon 3 of 5

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000459 AC: 115 AN: 250414 Hom.: 0 AF XY: 0.000495 AC XY: 67 AN XY: 135296

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00256

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000350 AC: 512 AN: 1461524 Hom.: 0 Cov.: 31 AF XY: 0.000404 AC XY: 294 AN XY: 727058

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00101

Gnomad4 SAS exome AF: 0.00135

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.000301

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74460

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000227 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000371 AC: 45

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Apr 02, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Mar 17, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 -

not specified Uncertain:1

Oct 16, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LAMA2 c.4993G>A (p.Gly1665Arg) results in a non-conservative amino acid change located in the laminin alpha, domain I (IPR009254) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 250414 control chromosomes, predominantly at a frequency of 0.0026 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in LAMA2 causing Laminin Alpha 2-Related Dystrophy phenotype (0.0022), suggesting that the variant may be a benign polymorphism found primarily in populations of East Asian origin. c.4993G>A has been reported in the literature in an individual suspected of Laminin Alpha 2-Related Dystrophy (Patel_2021). This report does not provide unequivocal conclusions about association of the variant with Laminin Alpha 2-Related Dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34925456). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Two submitters classified the variant as likely benign and one as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

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. -

Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 Uncertain:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

LAMA2-related muscular dystrophy Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	.;T;T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.7	.;.;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.3	.;.;N
REVEL	Benign	0.086
Sift	Benign	0.31	.;.;T
Polyphen		0.039	.;.;B
Vest4		0.21
MutPred		0.63		Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);
MVP		0.49
MPC		0.12
ClinPred		0.026	T
GERP RS		5.7
Varity_R		0.16
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs373997222; hg19: chr6-129704300; COSMIC: COSV70338457;