rs151009169

chr6-129438679-G-Achr6-129438679-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000426.4(LAMA2):c.6002G>A(p.Arg2001Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,608,142 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 3.39

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069534183).
• BP6: Variant 6-129438679-G-A is Benign according to our data. Variant chr6-129438679-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197453.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}. Variant chr6-129438679-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00027 (41/151946) while in subpopulation EAS AF= 0.00559 (29/5184). AF 95% confidence interval is 0.004. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.6002G>A	p.Arg2001Lys	missense_variant	42/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.6002G>A	p.Arg2001Lys	missense_variant	42/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.6002G>A	p.Arg2001Lys	missense_variant	42/65	5	NM_000426.4
LAMA2	ENST00000618192.5	c.6266G>A	p.Arg2089Lys	missense_variant	43/66	5		P1
LAMA2	ENST00000617695.5	c.6002G>A	p.Arg2001Lys	missense_variant	42/64	5

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 151826 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000460

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00558

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000271 AC: 68 AN: 250614 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135472

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00348

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000111 AC: 161 AN: 1456196 Hom.: 1 Cov.: 28 AF XY: 0.000101 AC XY: 73 AN XY: 724786

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00225

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.000270 AC: 41 AN: 151946 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74270

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00559

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000244 Hom.: 1

Bravo AF: 0.000230

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000264 AC: 32

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2017	A variant of uncertain significance has been identified in the LAMA2 gene. The R2001K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R2001K variant is observed in 29/8596 (0.3%) alleles from individuals of East Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species. However, the R2001K variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 10, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 30, 2022	BP4 -

LAMA2-related muscular dystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

LAMA2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 18, 2022

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	0.090
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	18
Dann	Benign	0.95
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.56	T;T;T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.0070	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.80	D
PrimateAI	Benign	0.41	T
Polyphen		0.028	.;.;B
Vest4		0.23
MVP		0.49
MPC		0.12
ClinPred		0.017	T
GERP RS		4.7
Varity_R		0.12
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: rs151009169; hg19: chr6-129759824; COSMIC: COSV70339292; COSMIC: COSV70339292;