2-219484160-C-T

Variant names:

• chr2-219484160-C-T
• rs587777672
• NM_005876.5:c.6697C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005876.5(SPEG):​c.6697C>T​(p.Gln2233*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPEG NM_005876.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.865

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]

ASIC4-AS1 (HGNC:40960): (ASIC4 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-219484160-C-T is Pathogenic according to our data. Variant chr2-219484160-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 144077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219484160-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPEG	NM_005876.5	c.6697C>T	p.Gln2233*	stop_gained	Exon 30 of 41	ENST00000312358.12	NP_005867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPEG	ENST00000312358.12	c.6697C>T	p.Gln2233*	stop_gained	Exon 30 of 41	5	NM_005876.5	ENSP00000311684.7
SPEG	ENST00000485813.5	n.5940C>T		non_coding_transcript_exon_variant	Exon 28 of 39	5
ASIC4-AS1	ENST00000429882.1	n.183-1751G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myopathy, centronuclear, 5 Pathogenic:2

Jul 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 07, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Sep 19, 2024

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.Gln2233*) in the SPEG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPEG are known to be pathogenic (PMID: 19118250, 25087613). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with centronuclear myopathy (PMID: 25087613). ClinVar contains an entry for this variant (Variation ID: 144077). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Benign	0.95
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.053	N
Vest4		0.55
GERP RS		-4.4

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777672; hg19: chr2-220348882;