Genetic Variant NM_005876.5:c.92C>A (chr2-219435069-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005876.5(SPEG):c.92C>A(p.Ala31Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,320,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A31A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

SPEG
NM_005876.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.216

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

myopathy, centronuclear, 5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
autosomal recessive centronuclear myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SPEG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36060274).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005876.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPEG	NM_005876.5	MANE Select	c.92C>A	p.Ala31Asp	missense	Exon 1 of 41	NP_005867.3
SPEG	NM_001438924.1		c.92C>A	p.Ala31Asp	missense	Exon 1 of 11	NP_001425853.1
SPEG	NM_001438925.1		c.92C>A	p.Ala31Asp	missense	Exon 1 of 10	NP_001425854.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPEG	ENST00000312358.12	TSL:5 MANE Select	c.92C>A	p.Ala31Asp	missense	Exon 1 of 41	ENSP00000311684.7	Q15772-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000151

AC:

AN:

1320262

Hom.:

Cov.:

AF XY:

0.00000308

AC XY:

AN XY:

649778

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26276

American (AMR)

AF:

0.0000392

AC:

AN:

25506

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22464

East Asian (EAS)

AF:

0.0000340

AC:

AN:

29372

South Asian (SAS)

AF:

0.00

AC:

AN:

71792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32464

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3976

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1053492

Other (OTH)

AF:

0.00

AC:

AN:

54920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.46

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.36

MetaSVM

Benign

-0.50

MutationAssessor

Benign

0.55

PhyloP100

0.22

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-1.9

REVEL

Benign

0.26

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.28

MutPred

0.32

Gain of ubiquitination at K28 (P = 0.0372)

MVP

0.33

MPC

1.1

ClinPred

0.50

GERP RS

4.9

PromoterAI

-0.029

Neutral

(source)

Varity_R

0.53

gMVP

0.40

Mutation Taster

=79/21

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over