2-219488262-C-T

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.7810C>T(p.Leu2604Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00411 in 1,613,486 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L2604L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0054 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0040 ( 11 hom. )

Consequence

SPEG
NM_005876.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 4.13

Publications

3 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 links:

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

ASIC4-AS1 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=0.016540855).

BP6

Variant 2-219488262-C-T is Benign according to our data. Variant chr2-219488262-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 374595.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00542 (826/152292) while in subpopulation AFR AF = 0.00936 (389/41554). AF 95% confidence interval is 0.00859. There are 6 homozygotes in GnomAd4. There are 390 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPEG	NM_005876.5 link	c.7810C>T	p.Leu2604Phe	missense_variant	Exon 32 of 41	ENST00000312358.12	NP_005867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SPEG	ENST00000312358.12 link	c.7810C>T	p.Leu2604Phe	missense_variant	Exon 32 of 41	5	NM_005876.5	ENSP00000311684.7
SPEG	ENST00000485813.5 link	n.7053C>T		non_coding_transcript_exon_variant	Exon 30 of 39	5
ASIC4-AS1	ENST00000429882.1 link	n.183-5853G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.00544

AC:

828

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00941

Gnomad AMI

AF:

0.0495

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00469

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00308

AC:

767

AN:

248862

AF XY:

0.00301

show subpopulations

Gnomad AFR exome

AF:

0.00860

Gnomad AMR exome

AF:

0.00261

Gnomad ASJ exome

AF:

0.00259

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000373

Gnomad NFE exome

AF:

0.00434

Gnomad OTH exome

AF:

0.00281

GnomAD4 exome

AF:

0.00397

AC:

5808

AN:

1461194

Hom.:

Cov.:

AF XY:

0.00384

AC XY:

2795

AN XY:

726940

show subpopulations

African (AFR)

AF:

0.00825

AC:

276

AN:

33462

American (AMR)

AF:

0.00262

AC:

117

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00272

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86192

European-Finnish (FIN)

AF:

0.000358

AC:

AN:

53146

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00454

AC:

5044

AN:

1111784

Other (OTH)

AF:

0.00437

AC:

264

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

276

551

827

1102

1378

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

198

396

594

792

990

<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:

0.00542

AC:

826

AN:

152292

Hom.:

Cov.:

AF XY:

0.00524

AC XY:

390

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00936

AC:

389

AN:

41554

American (AMR)

AF:

0.00287

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00469

AC:

319

AN:

68032

Other (OTH)

AF:

0.00332

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

128

170

213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00309

Hom.:

Bravo

AF:

0.00578

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00707

AC:

ESP6500EA

AF:

0.00570

AC:

ExAC

AF:

0.00322

AC:

390

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00360

EpiControl

AF:

0.00551

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SPEG: BP4, BS2 -

Myopathy, centronuclear, 5

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 04, 2017

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SPEG-related disorder

Benign:1

May 31, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.069

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.80

M_CAP

Benign

0.051

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.73

MutationAssessor

Benign

-0.19

PhyloP100

4.1

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.7

REVEL

Benign

0.24

Sift

Benign

0.12

Sift4G

Uncertain

0.037

Polyphen

0.96

Vest4

0.41

MVP

0.50

MPC

1.0

ClinPred

0.028

GERP RS

4.7

Varity_R

0.10

gMVP

0.15

Mutation Taster

=95/5

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over