rs56173620

chr6-129401308-C-Achr6-129401308-C-Gchr6-129401308-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000426.4(LAMA2):c.5530C>A(p.Arg1844Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,610,812 control chromosomes in the GnomAD database, including 250 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1844C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (9 hom., cov: 33)
  • Exomes 𝑓: 0.016 (241 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.873

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045015514).
• BP6: Variant 6-129401308-C-A is Benign according to our data. Variant chr6-129401308-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92968.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=6, Uncertain_significance=1}. Variant chr6-129401308-C-A is described in Lovd as [Benign]. Variant chr6-129401308-C-A is described in Lovd as [Likely_benign]. Variant chr6-129401308-C-A is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.01 (1524/152248) while in subpopulation NFE AF= 0.0175 (1190/68006). AF 95% confidence interval is 0.0167. There are 9 homozygotes in gnomad4. There are 682 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.5530C>A	p.Arg1844Ser	missense_variant	38/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.5530C>A	p.Arg1844Ser	missense_variant	38/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.5530C>A	p.Arg1844Ser	missense_variant	38/65	5	NM_000426.4
LAMA2	ENST00000618192.5	c.5794C>A	p.Arg1932Ser	missense_variant	39/66	5		P1
LAMA2	ENST00000617695.5	c.5530C>A	p.Arg1844Ser	missense_variant	38/64	5

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1525 AN: 152130 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00871

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0104 AC: 2604 AN: 250736 Hom.: 29 AF XY: 0.0106 AC XY: 1442 AN XY: 135504

Gnomad AFR exome AF: 0.00339

Gnomad AMR exome AF: 0.00593

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00323

Gnomad FIN exome AF: 0.00483

Gnomad NFE exome AF: 0.0184

Gnomad OTH exome AF: 0.00900

GnomAD4 exome AF: 0.0160 AC: 23366 AN: 1458564 Hom.: 241 Cov.: 31 AF XY: 0.0157 AC XY: 11428 AN XY: 725826

Gnomad4 AFR exome AF: 0.00234

Gnomad4 AMR exome AF: 0.00566

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00350

Gnomad4 FIN exome AF: 0.00581

Gnomad4 NFE exome AF: 0.0196

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.0100 AC: 1524 AN: 152248 Hom.: 9 Cov.: 33 AF XY: 0.00916 AC XY: 682 AN XY: 74448

Gnomad4 AFR AF: 0.00289

Gnomad4 AMR AF: 0.00869

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00415

Gnomad4 NFE AF: 0.0175

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0155 Hom.: 24

Bravo AF: 0.00971

TwinsUK AF: 0.0205 AC: 76

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0171 AC: 147

ExAC AF: 0.0107 AC: 1297

Asia WGS AF: 0.00260 AC: 10 AN: 3478

EpiCase AF: 0.0152

EpiControl AF: 0.0142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 04, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 17, 2022	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2019	This variant is associated with the following publications: (PMID: 20207543, 9541105, 25256590, 27535533, 29706646) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	LAMA2: BP4, BS1, BS2 -

Polymicrogyria Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Sep 01, 2017

this variant was indentified in an individual with malformations of cortical development -

Merosin deficient congenital muscular dystrophy Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The heterozygous p.Arg1844Ser variant in LAMA2 has been reported in the compound heterozygous state, with a splice site mutation, in an individual with congenital muscular dystrophy (PMID: 20207543), but has also been identified in >1% of European (non-Finnish) chromosomes and 18 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive congenital muscular dystrophy. -

LAMA2-related muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Congenital muscular dystrophy due to partial LAMA2 deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 08, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	20
Dann	Uncertain	0.97
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.80	T;T;T
MetaRNN	Benign	0.0045	T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.97	N
PrimateAI	Benign	0.23	T
Polyphen		0.085	.;.;B
Vest4		0.21
MPC		0.11
ClinPred		0.0062	T
GERP RS		4.4
Varity_R		0.13
gMVP		0.20

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: rs56173620; hg19: chr6-129722453;