6-129440897-C-A

Position:

• chr6-129440897-C-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.6167C>A​(p.Thr2056Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00486 in 1,613,896 control chromosomes in the GnomAD database, including 342 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 0.026 (177 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (165 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.60

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]

ENSG00000226149 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017717183).
• BP6: Variant 6-129440897-C-A is Benign according to our data. Variant chr6-129440897-C-A is described in ClinVar as [Benign]. Clinvar id is 129439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129440897-C-A is described in Lovd as [Benign]. Variant chr6-129440897-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.6167C>A	p.Thr2056Lys	missense_variant	43/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.6167C>A	p.Thr2056Lys	missense_variant	43/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.6167C>A	p.Thr2056Lys	missense_variant	43/65	5	NM_000426.4	ENSP00000400365.2
LAMA2	ENST00000618192.5	c.6431C>A	p.Thr2144Lys	missense_variant	44/66	5		ENSP00000480802.2
LAMA2	ENST00000617695.5	c.6167C>A	p.Thr2056Lys	missense_variant	43/64	5		ENSP00000481744.2
ENSG00000226149	ENST00000665046.1	n.1331G>T		non_coding_transcript_exon_variant	10/10

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 3918 AN: 152162 Hom.: 176 Cov.: 32

Gnomad AFR AF: 0.0895

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00956

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.00671 AC: 1683 AN: 250744 Hom.: 66 AF XY: 0.00472 AC XY: 640 AN XY: 135486

Gnomad AFR exome AF: 0.0924

Gnomad AMR exome AF: 0.00397

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00267 AC: 3908 AN: 1461616 Hom.: 165 Cov.: 31 AF XY: 0.00232 AC XY: 1687 AN XY: 727128

Gnomad4 AFR exome AF: 0.0950

Gnomad4 AMR exome AF: 0.00465

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000126

Gnomad4 OTH exome AF: 0.00591

GnomAD4 genome AF: 0.0258 AC: 3933 AN: 152280 Hom.: 177 Cov.: 32 AF XY: 0.0254 AC XY: 1889 AN XY: 74456

Gnomad4 AFR AF: 0.0896

Gnomad4 AMR AF: 0.00954

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.00478 Hom.: 38

Bravo AF: 0.0292

ESP6500AA AF: 0.0876 AC: 386

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00813 AC: 987

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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 12, 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	0.051
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.79
DEOGEN2	Benign	0.012	.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.20	T;T;T
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.1	.;.;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.1	.;.;N
REVEL	Benign	0.031
Sift	Benign	1.0	.;.;T
Polyphen		0.0	.;.;B
Vest4		0.16
MVP		0.29
MPC		0.11
ClinPred		0.0011	T
GERP RS		1.8
Varity_R		0.037
gMVP		0.27

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: rs73775407; hg19: chr6-129762042;