22-37062546-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001282686.2(KCTD17):c.634C>T(p.Arg212Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0484 in 1,612,974 control chromosomes in the GnomAD database, including 2,227 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R212L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.036 ( 163 hom., cov: 32)

Exomes 𝑓: 0.050 ( 2064 hom. )

Consequence

KCTD17
NM_001282686.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.716

Publications

9 publications found

Variant links:

Genes affected

KCTD17 (HGNC:25705): (potassium channel tetramerization domain containing 17) This gene encodes a protein that belongs to a conserved family of potassium channel tetramerization domain (KCTD)-containing proteins. The encoded protein functions in ciliogenesis by acting as a substrate adaptor for the cullin3-based ubiquitin-conjugating enzyme E3 ligase, and targets trichoplein, a keratin-binding protein, for degradation via polyubiquitinylation. A mutation in this gene is associated with autosomal dominant myoclonic dystonia 26. [provided by RefSeq, Nov 2016]

KCTD17 Gene-Disease associations (from GenCC):

myoclonic dystonia 26
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
myoclonus-dystonia syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KCTD17 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024590492).

BP6

Variant 22-37062546-C-T is Benign according to our data. Variant chr22-37062546-C-T is described in ClinVar as Benign. ClinVar VariationId is 476040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0548 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282686.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCTD17	NM_001282684.2	MANE Select	c.897C>T	p.Pro299Pro	synonymous	Exon 9 of 9	NP_001269613.2
KCTD17	NM_001282686.2		c.634C>T	p.Arg212Trp	missense	Exon 6 of 6	NP_001269615.2
KCTD17	NM_024681.4		c.825C>T	p.Pro275Pro	synonymous	Exon 8 of 8	NP_078957.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCTD17	ENST00000403888.8	TSL:1 MANE Select	c.897C>T	p.Pro299Pro	synonymous	Exon 9 of 9	ENSP00000385096.4
KCTD17	ENST00000402077.8	TSL:1	c.825C>T	p.Pro275Pro	synonymous	Exon 8 of 8	ENSP00000384391.4
KCTD17	ENST00000610767.5	TSL:3	c.634C>T	p.Arg212Trp	missense	Exon 6 of 6	ENSP00000480699.2

Frequencies

GnomAD3 genomes

AF:

0.0364

AC:

5535

AN:

151936

Hom.:

163

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0104

Gnomad AMI

AF:

0.0901

Gnomad AMR

AF:

0.0399

Gnomad ASJ

AF:

0.0262

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.0420

Gnomad FIN

AF:

0.0171

Gnomad MID

AF:

0.0955

Gnomad NFE

AF:

0.0564

Gnomad OTH

AF:

0.0364

GnomAD2 exomes

AF:

0.0371

AC:

9267

AN:

249656

AF XY:

0.0394

show subpopulations

Gnomad AFR exome

AF:

0.00817

Gnomad AMR exome

AF:

0.0230

Gnomad ASJ exome

AF:

0.0242

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0188

Gnomad NFE exome

AF:

0.0544

Gnomad OTH exome

AF:

0.0423

GnomAD4 exome

AF:

0.0497

AC:

72573

AN:

1460920

Hom.:

2064

Cov.:

AF XY:

0.0497

AC XY:

36150

AN XY:

726720

show subpopulations

African (AFR)

AF:

0.00738

AC:

247

AN:

33470

American (AMR)

AF:

0.0231

AC:

1032

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.0250

AC:

652

AN:

26116

East Asian (EAS)

AF:

0.000151

AC:

AN:

39694

South Asian (SAS)

AF:

0.0448

AC:

3862

AN:

86162

European-Finnish (FIN)

AF:

0.0195

AC:

1039

AN:

53376

Middle Eastern (MID)

AF:

0.0662

AC:

371

AN:

5604

European-Non Finnish (NFE)

AF:

0.0564

AC:

62741

AN:

1111530

Other (OTH)

AF:

0.0435

AC:

2623

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

3964

7928

11893

15857

19821

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2298

4596

6894

9192

11490

<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:

0.0364

AC:

5528

AN:

152054

Hom.:

163

Cov.:

AF XY:

0.0345

AC XY:

2567

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.0104

AC:

431

AN:

41478

American (AMR)

AF:

0.0399

AC:

610

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0262

AC:

AN:

3468

East Asian (EAS)

AF:

0.000388

AC:

AN:

5154

South Asian (SAS)

AF:

0.0420

AC:

202

AN:

4806

European-Finnish (FIN)

AF:

0.0171

AC:

181

AN:

10600

Middle Eastern (MID)

AF:

0.0890

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0563

AC:

3827

AN:

67966

Other (OTH)

AF:

0.0361

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

253

505

758

1010

1263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0472

Hom.:

102

Bravo

AF:

0.0351

TwinsUK

AF:

0.0569

AC:

211

ALSPAC

AF:

0.0628

AC:

242

ESP6500AA

AF:

0.00953

AC:

ESP6500EA

AF:

0.0549

AC:

472

ExAC

AF:

0.0385

AC:

4677

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0577

EpiControl

AF:

0.0584

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Myoclonic dystonia 26 (2)

not provided (2)

KCTD17-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.10

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0025

PhyloP100

0.72

Sift4G

Pathogenic

0.0

Vest4

0.20

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over