rs587777673

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005876.5(SPEG):​c.4276C>G​(p.Arg1426Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

SPEG
NM_005876.5 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.437
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.35004675).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SPEGNM_005876.5 linkuse as main transcriptc.4276C>G p.Arg1426Gly missense_variant 18/41 ENST00000312358.12 NP_005867.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SPEGENST00000312358.12 linkuse as main transcriptc.4276C>G p.Arg1426Gly missense_variant 18/415 NM_005876.5 ENSP00000311684 P1Q15772-5
SPEGENST00000485069.1 linkuse as main transcriptn.1513C>G non_coding_transcript_exon_variant 2/22
SPEGENST00000485813.5 linkuse as main transcriptn.3519C>G non_coding_transcript_exon_variant 16/395

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 17, 2022This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1426 of the SPEG protein (p.Arg1426Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SPEG-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.045
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
21
DANN
Benign
0.96
DEOGEN2
Benign
0.067
T
Eigen
Benign
-0.74
Eigen_PC
Benign
-0.56
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Benign
0.79
T
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.35
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.90
L
MutationTaster
Benign
0.94
D
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-1.8
N
REVEL
Benign
0.26
Sift
Uncertain
0.012
D
Sift4G
Benign
0.14
T
Polyphen
0.025
B
Vest4
0.62
MutPred
0.62
Loss of MoRF binding (P = 0.0099);
MVP
0.72
MPC
1.0
ClinPred
0.39
T
GERP RS
2.9
Varity_R
0.18
gMVP
0.34

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587777673; hg19: chr2-220338454; API