2-219484160-C-T

Position:

• chr2-219484160-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005876.5(SPEG):​c.6697C>T​(p.Gln2233Ter) 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: Likely pathogenic criteria provided, single submitter P:2
• 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 12 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_single_submitter, 1 stars. Variant chr2-219484160-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPEG	NM_005876.5	c.6697C>T	p.Gln2233Ter	stop_gained	30/41	ENST00000312358.12	NP_005867.3
ASIC4-AS1	XR_923921.2	n.392-1751G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPEG	ENST00000312358.12	c.6697C>T	p.Gln2233Ter	stop_gained	30/41	5	NM_005876.5	ENSP00000311684	P1
ASIC4-AS1	ENST00000429882.1	n.183-1751G>A		intron_variant, non_coding_transcript_variant		3
SPEG	ENST00000485813.5	n.5940C>T		non_coding_transcript_exon_variant	28/39	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Myopathy, centronuclear, 5 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 07, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 19, 2021	- -

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
MutationTaster	Benign	1.0	A
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;