Variant 11-78174298-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001029859.3(KCTD21):c.257T>G(p.Phe86Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

KCTD21
NM_001029859.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.43

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCTD21	NM_001029859.3 linkuse as main transcript	c.257T>G	p.Phe86Cys	missense_variant	2/2	ENST00000340067.4	NP_001025030.1	Q4G0X4
KCTD21	XM_047426803.1 linkuse as main transcript	c.365T>G	p.Phe122Cys	missense_variant	3/3		XP_047282759.1
KCTD21	XM_006718517.3 linkuse as main transcript	c.257T>G	p.Phe86Cys	missense_variant	3/3		XP_006718580.1	Q4G0X4
KCTD21	XM_006718518.4 linkuse as main transcript	c.257T>G	p.Phe86Cys	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.257T>G	p.Phe86Cys	missense_variant	2/2	1	NM_001029859.3	ENSP00000339340.3		Q4G0X4

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000958

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251308

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000331

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000196

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:

0.000958

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.000144

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

Aug 05, 2024

The c.257T>G (p.F86C) alteration is located in exon 2 (coding exon 1) of the KCTD21 gene. This alteration results from a T to G substitution at nucleotide position 257, causing the phenylalanine (F) at amino acid position 86 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.87

D;D;.;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.94

D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

4.0

H;.;.;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.3

D;D;D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;.;.;.

Polyphen

1.0

D;.;.;.

Vest4

0.94

MutPred

0.80

Loss of stability (P = 0.0959);Loss of stability (P = 0.0959);Loss of stability (P = 0.0959);Loss of stability (P = 0.0959);

MVP

0.99

MPC

1.3

ClinPred

1.0

GERP RS

5.9

Varity_R

0.85

gMVP

0.89

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