rs587777674

Positions:

• chr2-219469370-ATGACACAGTGTACGTGTCTGGGAAGTTCCCCGGGAG-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_005876.5(SPEG):​c.3709_3715+29del variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPEG NM_005876.5 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32

Genes affected

SPEG (HGNC:16901): (striated muscle enriched protein kinase) This gene encodes a protein with similarity to members of the myosin light chain kinase family. This protein family is required for myocyte cytoskeletal development. Along with the desmin gene, expression of this gene may be controlled by the desmin locus control region. Mutations in this gene are associated with centronuclear myopathy 5. [provided by RefSeq, Jun 2016]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-219469370-ATGACACAGTGTACGTGTCTGGGAAGTTCCCCGGGAG-A is Pathogenic according to our data. Variant chr2-219469370-ATGACACAGTGTACGTGTCTGGGAAGTTCCCCGGGAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 144079.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-219469370-ATGACACAGTGTACGTGTCTGGGAAGTTCCCCGGGAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPEG	NM_005876.5	c.3709_3715+29del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	13/41	ENST00000312358.12	NP_005867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPEG	ENST00000312358.12	c.3709_3715+29del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	13/41	5	NM_005876.5	ENSP00000311684	P1
SPEG	ENST00000485813.5	n.2952_2958+29del		splice_donor_variant, splice_donor_5th_base_variant, non_coding_transcript_exon_variant, intron_variant	11/39	5

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: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Myopathy, centronuclear, 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 07, 2014

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777674; hg19: chr2-220334092;