Genetic Variant KCTD1:p.Glu816Lys (chr18-26455895-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001142730.3(KCTD1):c.2446G>A(p.Glu816Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000378 in 1,612,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

KCTD1
NM_001142730.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.82

Variant links:

Genes affected

KCTD1 (HGNC:18249): (potassium channel tetramerization domain containing 1) This gene encodes a protein containing a BTB (Broad-complex, tramtrack and bric a brac), also known as a POZ (POxvirus and zinc finger) protein-protein interaction domain. The encoded protein negatively regulates the AP-2 family of transcription factors and the Wnt signaling pathway. A mechanism for the modulation of Wnt signaling has been proposed in which the encoded protein enhances ubiquitination and degradation of the beta-catenin protein. Mutations in this gene have been identified in Scalp-ear-nipple (SEN) syndrome. [provided by RefSeq, May 2017]

KCTD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32764417).

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCTD1	NM_001142730.3 link	c.2446G>A	p.Glu816Lys	missense_variant	Exon 5 of 5	ENST00000580059.7	NP_001136202.1	Q719H9A0A2U3U043

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCTD1	ENST00000580059.7 link	c.2446G>A	p.Glu816Lys	missense_variant	Exon 5 of 5	3	NM_001142730.3	ENSP00000463041.2		A0A2U3U043

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

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:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250742

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135558

show subpopulations

Gnomad AFR exome

AF:

0.000433

Gnomad AMR exome

AF:

0.0000290

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:

0.0000281

AC:

AN:

1460676

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726416

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.000131

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.000410

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:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2446G>A (p.E816K) alteration is located in exon 5 (coding exon 5) of the KCTD1 gene. This alteration results from a G to A substitution at nucleotide position 2446, causing the glutamic acid (E) at amino acid position 816 to be replaced by a lysine (K). 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

0.98

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.090

T;T;T;T;.;T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

0.0083

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

.;.;D;.;D;D;D

M_CAP

Benign

0.040

MetaRNN

Benign

0.27

T;T;T;T;T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.4

M;M;M;M;.;.;.

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.7

.;.;N;N;.;.;.

REVEL

Uncertain

0.47

Sift

Benign

0.072

.;.;T;T;.;.;.

Sift4G

Benign

0.18

T;T;T;T;.;.;.

Polyphen

0.0080

B;B;B;B;.;.;.

Vest4

0.53

MVP

0.89

MPC

0.68

ClinPred

0.15

GERP RS

5.1

Varity_R

0.51

gMVP

0.75

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