rs1554301637

Variant names:

• chr6-129464288-AGTCCTCAGGTGGAAGATAGTGAGGGGACTATTCAATTTGATGGAGAAGGTTATGCATTGGTCAGCCGTCCCATTCGCTGGTACCCCAACATCTCCACTGTCATGTTCAAGTTCAGAACATTTTCTTCGAGTGCTCTTCTGATGTATCTTGCCACACGAGACCT-A
• rs1554301637
• NM_000426.4:c.6993_7155del

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3 PP5_Moderate

The NM_000426.4(LAMA2):​c.6993_7155del variant causes a exon loss, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LAMA2 NM_000426.4 exon_loss, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.48
• 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 3 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 6-129464288-AGTCCTCAGGTGGAAGATAGTGAGGGGACTATTCAATTTGATGGAGAAGGTTATGCATTGGTCAGCCGTCCCATTCGCTGGTACCCCAACATCTCCACTGTCATGTTCAAGTTCAGAACATTTTCTTCGAGTGCTCTTCTGATGTATCTTGCCACACGAGACCT-A is Pathogenic according to our data. Variant chr6-129464288-AGTCCTCAGGTGGAAGATAGTGAGGGGACTATTCAATTTGATGGAGAAGGTTATGCATTGGTCAGCCGTCCCATTCGCTGGTACCCCAACATCTCCACTGTCATGTTCAAGTTCAGAACATTTTCTTCGAGTGCTCTTCTGATGTATCTTGCCACACGAGACCT-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 266109.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.6993_7155del		exon_loss_variant, splice_region_variant	Exon 50 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.6993_7155del		exon_loss_variant, splice_region_variant	Exon 50 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.6993-1_7154del	p.Ser2331_Leu2385delinsArg	splice_acceptor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 50 of 65	5	NM_000426.4	ENSP00000400365.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Merosin deficient congenital muscular dystrophy Pathogenic:1

Jan 01, 2014

Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5

Splicing

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

Other links and lift over

dbSNP: rs1554301637; hg19: chr6-129785433;