rs886039482

Variant names:

• chr6-129453044-CA-C
• rs886039482
• NM_000426.4:c.6488delA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000426.4(LAMA2):​c.6488delA​(p.Lys2163ArgfsTer12) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000479 in 1,460,392 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: LAMA2 NM_000426.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.63
• Publications: 2 publications found

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]

LAMA2 Gene-Disease associations (from GenCC):

• congenital merosin-deficient muscular dystrophy 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
• LAMA2-related muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy, limb-girdle, autosomal recessive 23

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000226149 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 6-129453044-CA-C is Pathogenic according to our data. Variant chr6-129453044-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 265332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.6488delA	p.Lys2163ArgfsTer12	frameshift_variant	Exon 46 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.6488delA	p.Lys2163ArgfsTer12	frameshift_variant	Exon 46 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.6488delA	p.Lys2163ArgfsTer12	frameshift_variant	Exon 46 of 65	5	NM_000426.4	ENSP00000400365.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460392 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726582

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53254

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111044

Other (OTH) AF: 0.00 AC: 0 AN: 60322

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Merosin deficient congenital muscular dystrophy Pathogenic:2

-

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LAMA2-related muscular dystrophy Pathogenic:1

Dec 15, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys2163Argfs*12) in the LAMA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the homozygous state in an individual  affected with merosin deficient congenital muscular dystrophy (PMID: 20207543). ClinVar contains an entry for this variant (Variation ID: 265332). Loss-of-function variants in LAMA2 are known to be pathogenic (PMID: 18700894). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Feb 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as one of the most common pathogenic variants in LAMA2 with greater than 15 entries in the LOVD database (Oliveira et al., 2018); Not observed in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32444167, 30055037, 20207543, 32860008) -

LAMA2-related disorder Pathogenic:1

Mar 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The LAMA2 c.6488delA variant is predicted to result in a frameshift and premature protein termination (p.Lys2163Argfs*12). This variant is one of the most common pathogenic variants in LAMA2 (Abdel Aleem et al 2020. PubMed ID: 32444167; Oliveira et al. 2018. PubMed ID: 30055037). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in LAMA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.6
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886039482; hg19: chr6-129774189;