chr2-200490173-A-C

Position:

• chr2-200490173-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000359878.8(KCTD18):​c.1208T>G​(p.Leu403Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCTD18 ENST00000359878.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.375

Genes affected

KCTD18 (HGNC:26446): (potassium channel tetramerization domain containing 18) Predicted to be involved in protein homooligomerization. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06298503).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCTD18	NM_152387.4	c.1208T>G	p.Leu403Arg	missense_variant	7/7	ENST00000359878.8	NP_689600.2
KCTD18	NM_001321547.2	c.1208T>G	p.Leu403Arg	missense_variant	7/7		NP_001308476.1
KCTD18	NM_001321548.2	c.581T>G	p.Leu194Arg	missense_variant	7/7		NP_001308477.1
KCTD18	NM_001321550.2	c.581T>G	p.Leu194Arg	missense_variant	7/7		NP_001308479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCTD18	ENST00000359878.8	c.1208T>G	p.Leu403Arg	missense_variant	7/7	1	NM_152387.4	ENSP00000352941.3
KCTD18	ENST00000409157.5	c.1208T>G	p.Leu403Arg	missense_variant	7/7	1		ENSP00000386751.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

KCTD18-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2023

The KCTD18 c.1208T>G variant is predicted to result in the amino acid substitution p.Leu403Arg. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.7
DANN	Benign	0.86
DEOGEN2	Benign	0.0042	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.38	.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.063	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.34	N;N
REVEL	Benign	0.019
Sift	Benign	0.12	T;T
Sift4G	Benign	0.061	T;T
Polyphen		0.0090	B;B
Vest4		0.16
MutPred		0.17		Gain of solvent accessibility (P = 0.0018);Gain of solvent accessibility (P = 0.0018);
MVP		0.28
MPC		0.29
ClinPred		0.028	T
GERP RS		2.3
Varity_R		0.046
gMVP		0.15

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: chr2-201354896;