22-37062546-C-G

Variant names:

• chr22-37062546-C-G
• rs116956945
• NM_001282684.2:c.897C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001282686.2(KCTD17):​c.634C>G​(p.Arg212Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R212W) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCTD17 NM_001282686.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.716
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17979911).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCTD17	NM_001282684.2	MANE Select	c.897C>G	p.Pro299Pro	synonymous	Exon 9 of 9	NP_001269613.2
	KCTD17	NM_001282686.2		c.634C>G	p.Arg212Gly	missense	Exon 6 of 6	NP_001269615.2
	KCTD17	NM_024681.4		c.825C>G	p.Pro275Pro	synonymous	Exon 8 of 8	NP_078957.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCTD17	ENST00000403888.8	TSL:1 MANE Select	c.897C>G	p.Pro299Pro	synonymous	Exon 9 of 9	ENSP00000385096.4
	KCTD17	ENST00000402077.8	TSL:1	c.825C>G	p.Pro275Pro	synonymous	Exon 8 of 8	ENSP00000384391.4
	KCTD17	ENST00000610767.5	TSL:3	c.634C>G	p.Arg212Gly	missense	Exon 6 of 6	ENSP00000480699.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461182 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 726876

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111702

Other (OTH) AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	7.8
DANN	Benign	0.82
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.18	T
PhyloP100		0.72
Sift4G	Uncertain	0.0050	D
Vest4		0.37
MVP		0.58
GERP RS		1.5
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs116956945; hg19: chr22-37458586;