2-219483098-C-T

Position:

chr2-219483098-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BS1_Supporting

The NM_005876.5(SPEG):c.5635C>T(p.Arg1879Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000148 in 1,604,308 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

SPEG
NM_005876.5 missense, splice_region

Scores

Splicing: ADA: 0.9949

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.69

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]

SPEG links:

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

ASIC4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00021 (32/152224) while in subpopulation AMR AF= 0.000588 (9/15306). AF 95% confidence interval is 0.000306. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPEG	NM_005876.5 linkuse as main transcript	c.5635C>T	p.Arg1879Cys	missense_variant, splice_region_variant	30/41	ENST00000312358.12
ASIC4-AS1	XR_923921.2 linkuse as main transcript	n.392-689G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPEG	ENST00000312358.12 linkuse as main transcript	c.5635C>T	p.Arg1879Cys	missense_variant, splice_region_variant	30/41	5	NM_005876.5	P1	Q15772-5
ASIC4-AS1	ENST00000429882.1 linkuse as main transcript	n.183-689G>A		intron_variant, non_coding_transcript_variant		3
SPEG	ENST00000485813.5 linkuse as main transcript	n.4878C>T		splice_region_variant, non_coding_transcript_exon_variant	28/39	5

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000177

AC:

AN:

231628

Hom.:

AF XY:

0.000172

AC XY:

AN XY:

127800

show subpopulations

Gnomad AFR exome

AF:

0.000220

Gnomad AMR exome

AF:

0.000562

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000336

Gnomad FIN exome

AF:

0.0000585

Gnomad NFE exome

AF:

0.000134

Gnomad OTH exome

AF:

0.000524

GnomAD4 exome

AF:

0.000141

AC:

205

AN:

1452084

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

106

AN XY:

722328

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.000790

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000351

Gnomad4 FIN exome

AF:

0.0000212

Gnomad4 NFE exome

AF:

0.000118

Gnomad4 OTH exome

AF:

0.000382

GnomAD4 genome

AF:

0.000210

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000168

Hom.:

Bravo

AF:

0.000193

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000502

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000149

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1879 of the SPEG protein (p.Arg1879Cys). This variant is present in population databases (rs113853448, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with SPEG-related conditions. ClinVar contains an entry for this variant (Variation ID: 1376292). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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

Pathogenic

0.72

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.039

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.0

REVEL

Benign

0.20

Sift

Benign

0.065

Sift4G

Benign

0.11

Polyphen

0.95

Vest4

0.72

MVP

0.29

MPC

1.6

ClinPred

0.18

GERP RS

5.0

Varity_R

0.25

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.84

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over