2-219488262-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -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).

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

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 Benign. Variant got -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 id is 374595.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

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	Q15772-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPEG	ENST00000312358.12 link	c.7810C>T	p.Leu2604Phe	missense_variant	Exon 32 of 41	5	NM_005876.5	ENSP00000311684.7	Q15772-5
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

GnomAD3 exomes

AF:

0.00308

AC:

767

AN:

248862

Hom.:

AF XY:

0.00301

AC XY:

406

AN XY:

135054

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 SAS exome

AF:

0.0000982

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

Gnomad4 AFR exome

AF:

0.00825

Gnomad4 AMR exome

AF:

0.00262

Gnomad4 ASJ exome

AF:

0.00272

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.000358

Gnomad4 NFE exome

AF:

0.00454

Gnomad4 OTH exome

AF:

0.00437

GnomAD4 genome

AF:

0.00542

AC:

826

AN:

152292

Hom.:

Cov.:

AF XY:

0.00524

AC XY:

390

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00936

Gnomad4 AMR

AF:

0.00287

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.000376

Gnomad4 NFE

AF:

0.00469

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00402

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

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 -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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

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

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.

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