Variant chr11-78174520-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001029859.3(KCTD21):c.35A>C(p.Lys12Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,294 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KCTD21
NM_001029859.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.21

Variant links:

Genes affected

KCTD21 (HGNC:27452): (potassium channel tetramerization domain containing 21) Enables cullin family protein binding activity; histone deacetylase binding activity; and identical protein binding activity. Involved in negative regulation of smoothened signaling pathway and ubiquitin-dependent protein catabolic process. [provided by Alliance of Genome Resources, Apr 2022]

KCTD21 links:

KCTD21-AS1 (HGNC:):

KCTD21-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30965698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCTD21	NM_001029859.3 linkuse as main transcript	c.35A>C	p.Lys12Thr	missense_variant	2/2	ENST00000340067.4	NP_001025030.1	Q4G0X4
KCTD21	XM_047426803.1 linkuse as main transcript	c.143A>C	p.Lys48Thr	missense_variant	3/3		XP_047282759.1
KCTD21	XM_006718517.3 linkuse as main transcript	c.35A>C	p.Lys12Thr	missense_variant	3/3		XP_006718580.1	Q4G0X4
KCTD21	XM_006718518.4 linkuse as main transcript	c.35A>C	p.Lys12Thr	missense_variant	2/2		XP_006718581.1	Q4G0X4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCTD21	ENST00000340067.4 linkuse as main transcript	c.35A>C	p.Lys12Thr	missense_variant	2/2	1	NM_001029859.3	ENSP00000339340.3		Q4G0X4

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151956

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461338

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726976

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151956

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74224

show subpopulations

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2024

The c.35A>C (p.K12T) alteration is located in exon 2 (coding exon 1) of the KCTD21 gene. This alteration results from a A to C substitution at nucleotide position 35, causing the lysine (K) at amino acid position 12 to be replaced by a threonine (T). 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

-0.068

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;T;.;T;.;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.027

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

D;D;D;D;D;D

M_CAP

Benign

0.0064

MetaRNN

Benign

0.31

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.94

N;.;.;.;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.15

N;N;N;N;N;N

REVEL

Benign

0.22

Sift

Benign

1.0

T;T;T;T;T;T

Sift4G

Benign

0.59

T;.;.;.;.;.

Polyphen

0.027

B;.;.;.;.;.

Vest4

0.49

MutPred

0.55

Loss of ubiquitination at K12 (P = 0.0199);Loss of ubiquitination at K12 (P = 0.0199);Loss of ubiquitination at K12 (P = 0.0199);Loss of ubiquitination at K12 (P = 0.0199);Loss of ubiquitination at K12 (P = 0.0199);Loss of ubiquitination at K12 (P = 0.0199);

MVP

0.34

MPC

0.47

ClinPred

0.86

GERP RS

5.6

Varity_R

0.071

gMVP

0.73

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