rs1221715098

Variant names:

• chr6-129460329-G-A
• rs1221715098
• NM_000426.4:c.6992+5G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000426.4(LAMA2):​c.6992+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000103 in 1,459,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: LAMA2 NM_000426.4 splice_region, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 4.69
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 6-129460329-G-A is Pathogenic according to our data. Variant chr6-129460329-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 546142.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.6992+5G>A		splice_region_variant, intron_variant	Intron 49 of 64	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.6992+5G>A		splice_region_variant, intron_variant	Intron 49 of 63		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.6992+5G>A		splice_region_variant, intron_variant	Intron 49 of 64	5	NM_000426.4	ENSP00000400365.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250460 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1459702 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726256

African (AFR) AF: 0.00 AC: 0 AN: 33360

American (AMR) AF: 0.0000224 AC: 1 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1110438

Other (OTH) AF: 0.0000166 AC: 1 AN: 60250

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

May 29, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6992+5G>A variant in the LAMA2 gene has been reported previously in the heterozygous state with a second LAMA2 variant in an individual with limb girdle muscular dystrophy, however, segregation studies to confirm phase were only performed on one parent (Harris et al., 2017). This variant is predicted to destroy the splice donor site in intron 49. Both in silico predictors and evolutionary conservation support a deleterious effect in this gene for which loss-of-function is a known mechanism for disease. The c.6992+5G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.6992+5G>A as a likely pathogenic variant. -

Muscular dystrophy, limb-girdle, autosomal recessive 23 Pathogenic:1

-

Institute of Human Genetics, University of Wuerzburg

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Merosin deficient congenital muscular dystrophy Uncertain:1

Mar 01, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

LAMA2-related muscular dystrophy Uncertain:1

Apr 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 49 of the LAMA2 gene. It does not directly change the encoded amino acid sequence of the LAMA2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has been observed in individual(s) with limb girdle muscular dystrophy (PMID: 28877744). ClinVar contains an entry for this variant (Variation ID: 546142). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

LAMA2-related disorder Uncertain:1

Mar 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LAMA2 c.6992+5G>A variant is predicted to interfere with splicing. This variant has been reported in the heterozygous state (along with a second variant) in an individual with white matter changes (Table 1, individual 32, Harris et al. 2017. PubMed ID: 28877744). A skin biopsy for this individual demonstrated partial absence of laminin a2. In the gnomAD public population database this variant has been reported in one of ~250,000 alleles (https://gnomad.broadinstitute.org/variant/6-129781474-G-A), and is interpreted as uncertain significance and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/546142/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	21
DANN	Benign	0.73
PhyloP100		4.7
Mutation Taster		=57/43	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.80		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.80		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1221715098; hg19: chr6-129781474; COSMIC: COSV109442284;