rs786205860

Variant names:

• chr22-37057420-G-A
• rs786205860
• NM_001282684.2:c.413G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-37057420-G-A
• chr22-37057420-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001282684.2(KCTD17):​c.413G>A​(p.Arg138His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: KCTD17 NM_001282684.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.93

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• PP5: Variant 22-37057420-G-A is Pathogenic according to our data. Variant chr22-37057420-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 191372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCTD17	NM_001282684.2	c.413G>A	p.Arg138His	missense_variant	Exon 4 of 9	ENST00000403888.8	NP_001269613.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCTD17	ENST00000403888.8	c.413G>A	p.Arg138His	missense_variant	Exon 4 of 9	1	NM_001282684.2	ENSP00000385096.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152144 Hom.: 0 Cov.: 33 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152144 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74306

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myoclonic dystonia 26 Pathogenic:2

Jun 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 145 of the KCTD17 protein (p.Arg145His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with myoclonus-dystonia (PMID: 25983243). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 191372). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCTD17 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects KCTD17 function (PMID: 25983243). For these reasons, this variant has been classified as Pathogenic. -

May 12, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jul 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T;.;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	-0.040	T
MutationAssessor	Uncertain	2.9	.;M;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.8	.;D;D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		1.0, 0.95	.;D;P
Vest4		0.87
MutPred		0.51		Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);
MVP		0.77
MPC		2.2
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.56
gMVP		0.74

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: rs786205860; hg19: chr22-37453460;