22-37051815-G-A

Variant summary

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

The NM_001282684.2(KCTD17):c.55G>A(p.Ala19Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,284,934 control chromosomes in the GnomAD database, including 10,098 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. A19V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.12 (1092 hom., cov: 31)
  • Exomes 𝑓: 0.12 (9006 hom.)
• Consequence: KCTD17 NM_001282684.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.745

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=0.0011972487).
• BP6: Variant 22-37051815-G-A is Benign according to our data. Variant chr22-37051815-G-A is described in ClinVar as [Benign]. Clinvar id is 1168447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCTD17	NM_001282684.2	c.55G>A	p.Ala19Thr	missense_variant	1/9	ENST00000403888.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCTD17	ENST00000403888.8	c.55G>A	p.Ala19Thr	missense_variant	1/9	1	NM_001282684.2	A2
KCTD17	ENST00000402077.8	c.55G>A	p.Ala19Thr	missense_variant	1/8	1		A2
KCTD17	ENST00000610767.5	c.55G>A	p.Ala19Thr	missense_variant	1/6	3		P2
KCTD17	ENST00000421900.5			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17519 AN: 151616 Hom.: 1092 Cov.: 31

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.0857

Gnomad AMR AF: 0.0767

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.00271

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.0417

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.102

GnomAD3 exomes AF: 0.108 AC: 2472 AN: 22988 Hom.: 196 AF XY: 0.108 AC XY: 1628 AN XY: 15018

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0685

Gnomad ASJ exome AF: 0.0842

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.0923

GnomAD4 exome AF: 0.123 AC: 139051 AN: 1133208 Hom.: 9006 Cov.: 32 AF XY: 0.123 AC XY: 66996 AN XY: 546408

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.0623

Gnomad4 ASJ exome AF: 0.100

Gnomad4 EAS exome AF: 0.00109

Gnomad4 SAS exome AF: 0.101

Gnomad4 FIN exome AF: 0.157

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.109

GnomAD4 genome AF: 0.116 AC: 17538 AN: 151726 Hom.: 1092 Cov.: 31 AF XY: 0.115 AC XY: 8504 AN XY: 74162

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0766

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.00272

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.129

Gnomad4 OTH AF: 0.101

Alfa AF: 0.124 Hom.: 158

Bravo AF: 0.109

ExAC AF: 0.0437 AC: 994

Asia WGS AF: 0.0640 AC: 222 AN: 3454

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KCTD17-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 19, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2021

- -

Myoclonic dystonia 26 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0066	T;.;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.66	T;T;T
MetaRNN	Benign	0.0012	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.76	T
Sift4G	Benign	0.59	T;T;T
Polyphen		0.27, 0.18	.;B;B
Vest4		0.061
MPC		2.0
ClinPred		0.014	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.069
gMVP		0.14

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

Other links and lift over

dbSNP: rs113687833; hg19: chr22-37447855; COSMIC: COSV63248856; COSMIC: COSV63248856;