rs565137573

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005876.5(SPEG):c.116T>C(p.Val39Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,461,702 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0087 ( 20 hom., cov: 33)

Exomes 𝑓: 0.00068 ( 12 hom. )

Consequence

SPEG
NM_005876.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -2.17

Publications

2 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002774924).

BP6

Variant 2-219435093-T-C is Benign according to our data. Variant chr2-219435093-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287260.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00874 (1330/152168) while in subpopulation AFR AF = 0.0302 (1256/41528). AF 95% confidence interval is 0.0289. There are 20 homozygotes in GnomAd4. There are 630 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

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.116T>C	p.Val39Ala	missense	Exon 1 of 41	NP_005867.3
SPEG	NM_001438924.1		c.116T>C	p.Val39Ala	missense	Exon 1 of 11	NP_001425853.1
SPEG	NM_001438925.1		c.116T>C	p.Val39Ala	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.116T>C	p.Val39Ala	missense	Exon 1 of 41	ENSP00000311684.7	Q15772-5

Frequencies

GnomAD3 genomes

AF:

0.00873

AC:

1328

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0303

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

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:

0.000132

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.000551

AC:

AN:

56248

AF XY:

0.000399

show subpopulations

Gnomad AFR exome

AF:

0.0262

Gnomad AMR exome

AF:

0.000768

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000677

AC:

886

AN:

1309534

Hom.:

Cov.:

AF XY:

0.000562

AC XY:

362

AN XY:

643714

show subpopulations

African (AFR)

AF:

0.0292

AC:

755

AN:

25832

American (AMR)

AF:

0.00132

AC:

AN:

23514

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21564

East Asian (EAS)

AF:

0.00

AC:

AN:

29414

South Asian (SAS)

AF:

0.0000288

AC:

AN:

69370

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31938

Middle Eastern (MID)

AF:

0.000989

AC:

AN:

4044

European-Non Finnish (NFE)

AF:

0.00000667

AC:

AN:

1049398

Other (OTH)

AF:

0.00160

AC:

AN:

54460

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

110

164

219

274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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

AF:

0.00874

AC:

1330

AN:

152168

Hom.:

Cov.:

AF XY:

0.00847

AC XY:

630

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0302

AC:

1256

AN:

41528

American (AMR)

AF:

0.00333

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

67970

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

141

211

282

352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00617

Hom.:

Bravo

AF:

0.00967

ExAC

AF:

0.000680

AC:

Asia WGS

AF:

0.00116

AC:

AN:

3468

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.10

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.045

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.28

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-2.2

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.33

REVEL

Benign

0.048

Sift

Benign

0.96

Sift4G

Benign

0.58

Polyphen

0.0

Vest4

0.084

MVP

0.48

MPC

0.78

ClinPred

0.0045

GERP RS

-3.4

PromoterAI

0.051

Neutral

(source)

Varity_R

0.035

gMVP

0.085

Mutation Taster

=100/0

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over