Genetic Variant KCTD8:p.Asp203Tyr (chr4-44447917-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_198353.3(KCTD8):c.607G>T(p.Asp203Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,447,316 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

KCTD8
NM_198353.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.59

Variant links:

Genes affected

KCTD8 (HGNC:22394): (potassium channel tetramerization domain containing 8) Predicted to be involved in regulation of G protein-coupled receptor signaling pathway. Predicted to be located in cell projection; postsynaptic membrane; and presynaptic membrane. Predicted to be integral component of membrane. Predicted to be part of receptor complex. [provided by Alliance of Genome Resources, Apr 2022]

KCTD8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCTD8	NM_198353.3 link	c.607G>T	p.Asp203Tyr	missense_variant	Exon 1 of 2	ENST00000360029.4	NP_938167.1	Q6ZWB6
KCTD8	XM_011513690.4 link	c.607G>T	p.Asp203Tyr	missense_variant	Exon 1 of 3		XP_011511992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCTD8	ENST00000360029.4 link	c.607G>T	p.Asp203Tyr	missense_variant	Exon 1 of 2	1	NM_198353.3	ENSP00000353129.3		Q6ZWB6

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151702

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:

0.00000154

AC:

AN:

1295614

Hom.:

Cov.:

AF XY:

0.00000158

AC XY:

AN XY:

633990

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:

0.00000194

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151702

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74094

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:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.607G>T (p.D203Y) alteration is located in exon 1 (coding exon 1) of the KCTD8 gene. This alteration results from a G to T substitution at nucleotide position 607, causing the aspartic acid (D) at amino acid position 203 to be replaced by a tyrosine (Y). 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

0.25

BayesDel_addAF

Benign

-0.00071

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Benign

0.16

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.1

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.1

REVEL

Benign

0.15

Sift

Benign

0.068

Sift4G

Uncertain

0.0080

Polyphen

0.97

Vest4

0.68

MutPred

0.28

Loss of ubiquitination at K204 (P = 0.0149);

MVP

0.56

ClinPred

0.98

GERP RS

4.2

Varity_R

0.21

gMVP

0.65

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