22-37051766-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001282684.2(KCTD17):c.6G>C(p.Arg2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KCTD17 NM_001282684.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18806839).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCTD17	NM_001282684.2	c.6G>C	p.Arg2Ser	missense_variant	1/9	ENST00000403888.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCTD17	ENST00000403888.8	c.6G>C	p.Arg2Ser	missense_variant	1/9	1	NM_001282684.2	A2
KCTD17	ENST00000402077.8	c.6G>C	p.Arg2Ser	missense_variant	1/8	1		A2
KCTD17	ENST00000610767.5	c.6G>C	p.Arg2Ser	missense_variant	1/6	3		P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myoclonic dystonia 26 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 26, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with KCTD17-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 9 of the KCTD17 protein (p.Arg9Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0069	T;.;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.080
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.80	T;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	0.53	D;D
PrimateAI	Pathogenic	0.92	D
Sift4G	Benign	0.76	T;T;T
Polyphen		0.25, 0.28	.;B;B
Vest4		0.16
MutPred		0.37		Gain of phosphorylation at R9 (P = 0.0162);Gain of phosphorylation at R9 (P = 0.0162);Gain of phosphorylation at R9 (P = 0.0162);
MVP		0.41
MPC		1.8
ClinPred		0.41	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.19
gMVP		0.21

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: rs1924500203; hg19: chr22-37447806;