4-44175002-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198353.3(KCTD8):c.1210C>A(p.Pro404Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCTD8 NM_198353.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.59

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]

ACMG classification

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=0.21301103).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCTD8	NM_198353.3	c.1210C>A	p.Pro404Thr	missense_variant	2/2	ENST00000360029.4
KCTD8	XM_011513690.4	c.1294C>A	p.Pro432Thr	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCTD8	ENST00000360029.4	c.1210C>A	p.Pro404Thr	missense_variant	2/2	1	NM_198353.3	P1
KCTD8	ENST00000515268.1	c.418C>A	p.Pro140Thr	missense_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2023

The c.1210C>A (p.P404T) alteration is located in exon 2 (coding exon 2) of the KCTD8 gene. This alteration results from a C to A substitution at nucleotide position 1210, causing the proline (P) at amino acid position 404 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	0.15
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.95	D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.14
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.037	D
Polyphen		0.90	P
Vest4		0.27
MutPred		0.16		Gain of phosphorylation at P404 (P = 0.0235);
MVP		0.60
ClinPred		0.78	D
GERP RS		4.8
Varity_R		0.19
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-44177019; COSMIC: COSV63594466;