Genetic Variant NM_015353.3:c.136C>T (chr17-75047386-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015353.3(KCTD2):c.136C>T(p.Arg46Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000202 in 991,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000020 ( 0 hom. )

Consequence

KCTD2
NM_015353.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.192

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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=0.077929914).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCTD2	NM_015353.3 link	c.136C>T	p.Arg46Cys	missense_variant	Exon 1 of 6	ENST00000322444.7	NP_056168.1	Q14681Q8IYY2
KCTD2	NR_110834.2 link	n.76-33C>T		intron_variant	Intron 1 of 6
KCTD2	NR_110835.2 link	n.366-1834C>T		intron_variant	Intron 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCTD2	ENST00000322444.7 link	c.136C>T	p.Arg46Cys	missense_variant	Exon 1 of 6	1	NM_015353.3	ENSP00000312814.6		Q14681

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00127

AC:

AN:

786

Hom.:

AF XY:

0.00

AC XY:

AN XY:

426

show subpopulations

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00205

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000202

AC:

AN:

991556

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

467694

show subpopulations

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:

0.00000231

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.136C>T (p.R46C) alteration is located in exon 1 (coding exon 1) of the KCTD2 gene. This alteration results from a C to T substitution at nucleotide position 136, causing the arginine (R) at amino acid position 46 to be replaced by a cysteine (C). 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

Benign

0.20

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0040

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.72

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.078

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.55

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.19

REVEL

Benign

0.11

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.059

Polyphen

0.0020

Vest4

0.070

MutPred

0.41

Loss of methylation at R46 (P = 0.0021);

MVP

0.43

MPC

2.4

ClinPred

0.14

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.12

gMVP

0.37

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over