17-75047290-G-C

Position:

• chr17-75047290-G-C

Variant summary

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

The NM_015353.3(KCTD2):​c.40G>C​(p.Gly14Arg) variant causes a missense change. 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 (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCTD2 NM_015353.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.80

Genes affected

KCTD2 (HGNC:21294): (potassium channel tetramerization domain containing 2) Predicted to enable cullin family protein binding activity. Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Predicted to be part of Cul3-RING ubiquitin ligase complex. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

KCTD2 (HGNC:):

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=0.26381716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCTD2	NM_015353.3	c.40G>C	p.Gly14Arg	missense_variant	1/6	ENST00000322444.7	NP_056168.1
KCTD2	NR_110834.2	n.66G>C		non_coding_transcript_exon_variant	1/7
KCTD2	NR_110835.2	n.366-1930G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCTD2	ENST00000322444.7	c.40G>C	p.Gly14Arg	missense_variant	1/6	1	NM_015353.3	ENSP00000312814.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 998862 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 473852

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2022

The c.40G>C (p.G14R) alteration is located in exon 1 (coding exon 1) of the KCTD2 gene. This alteration results from a G to C substitution at nucleotide position 40, causing the glycine (G) at amino acid position 14 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-0.041
Eigen_PC	Benign	-0.013
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.69	N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.12
Sift	Benign	0.12	T
Sift4G	Benign	0.24	T
Polyphen		0.0020	B
Vest4		0.28
MutPred		0.34		Gain of methylation at G14 (P = 0.0082);
MVP		0.62
MPC		1.2
ClinPred		0.65	D
GERP RS		3.1
Varity_R		0.15
gMVP		0.22

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: rs1361393100; hg19: chr17-73043385;