rs1221715098

chr6-129460329-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3_Moderate PP5

The NM_000426.4(LAMA2):c.6992+5G>A variant causes a splice donor 5th base, 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_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 4.69

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PP3: Splicing scoreres supports a deletorius 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 submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.6992+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000421865.3
LAMA2	NM_001079823.2	c.6992+5G>A		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.6992+5G>A		splice_donor_5th_base_variant, intron_variant		5	NM_000426.4
	ENST00000665046.1	n.976-19077C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250460 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135356

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 29, 2018

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. -

Merosin deficient congenital muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 01, 2018

- -

LAMA2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2023

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1221715098; hg19: chr6-129781474;