rs116956945

Positions:

• chr22-37062546-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 8/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (163 hom., cov: 32)
  • Exomes 𝑓: 0.050 (2064 hom.)
• Consequence: KCTD17 NM_001282686.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.716

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCTD17	NM_001282684.2	c.897C>T	p.Pro299Pro	synonymous_variant	9/9	ENST00000403888.8	NP_001269613.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCTD17	ENST00000403888.8	c.897C>T	p.Pro299Pro	synonymous_variant	9/9	1	NM_001282684.2	ENSP00000385096.4
KCTD17	ENST00000402077.8	c.825C>T	p.Pro275Pro	synonymous_variant	8/8	1		ENSP00000384391.4
KCTD17	ENST00000610767.5	c.634C>T	p.Arg212Trp	missense_variant	6/6	3		ENSP00000480699.2
KCTD17	ENST00000456470.1	c.*68C>T		3_prime_UTR_variant	7/7	3		ENSP00000409638.1

Frequencies

GnomAD3 genomes AF: 0.0364 AC: 5535 AN: 151936 Hom.: 163 Cov.: 32

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

GnomAD3 exomes AF: 0.0371 AC: 9267 AN: 249656 Hom.: 256 AF XY: 0.0394 AC XY: 5321 AN XY: 135172

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 SAS exome AF: 0.0432

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.: 36 AF XY: 0.0497 AC XY: 36150 AN XY: 726720

Gnomad4 AFR exome AF: 0.00738

Gnomad4 AMR exome AF: 0.0231

Gnomad4 ASJ exome AF: 0.0250

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0448

Gnomad4 FIN exome AF: 0.0195

Gnomad4 NFE exome AF: 0.0564

Gnomad4 OTH exome AF: 0.0435

GnomAD4 genome AF: 0.0364 AC: 5528 AN: 152054 Hom.: 163 Cov.: 32 AF XY: 0.0345 AC XY: 2567 AN XY: 74310

Gnomad4 AFR AF: 0.0104

Gnomad4 AMR AF: 0.0399

Gnomad4 ASJ AF: 0.0262

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.0420

Gnomad4 FIN AF: 0.0171

Gnomad4 NFE AF: 0.0563

Gnomad4 OTH AF: 0.0361

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: 42

ESP6500EA AF: 0.0549 AC: 472

ExAC AF: 0.0385 AC: 4677

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.0577

EpiControl AF: 0.0584

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2021	- -

Myoclonic dystonia 26 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

KCTD17-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	13
DANN	Benign	0.87
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0025	T
Sift4G	Pathogenic	0.0	D
Vest4		0.20
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs116956945; hg19: chr22-37458586; COSMIC: COSV60983004; COSMIC: COSV60983004;