3-58501601-T-C

Position:

• chr3-58501601-T-C

Variant summary

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

The NM_001128214.2(KCTD6):​c.683T>C​(p.Phe228Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCTD6 NM_001128214.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

KCTD6 (HGNC:22235): (potassium channel tetramerization domain containing 6) Enables ankyrin binding activity; cullin family protein binding activity; and identical protein binding activity. Involved in negative regulation of smoothened signaling pathway and ubiquitin-dependent protein catabolic process. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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/exons	MANE	Protein	UniProt
KCTD6	NM_001128214.2	c.683T>C	p.Phe228Ser	missense_variant	3/3	ENST00000404589.8	NP_001121686.1
KCTD6	NM_153331.3	c.683T>C	p.Phe228Ser	missense_variant	2/2		NP_699162.3
KCTD6	XM_005264937.3	c.683T>C	p.Phe228Ser	missense_variant	3/3		XP_005264994.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCTD6	ENST00000404589.8	c.683T>C	p.Phe228Ser	missense_variant	3/3	2	NM_001128214.2	ENSP00000384948.3
KCTD6	ENST00000355076.6	c.683T>C	p.Phe228Ser	missense_variant	2/2	1		ENSP00000347188.6
KCTD6	ENST00000490264.1	c.683T>C	p.Phe228Ser	missense_variant	4/4	5		ENSP00000417490.1

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

Jul 09, 2024

The c.683T>C (p.F228S) alteration is located in exon 2 (coding exon 2) of the KCTD6 gene. This alteration results from a T to C substitution at nucleotide position 683, causing the phenylalanine (F) at amino acid position 228 to be replaced by a serine (S). 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	1.0
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;T
Eigen	Benign	0.067
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	.;.;D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.31	B;B;B
Vest4		0.79
MutPred		0.31		Gain of disorder (P = 0.0019);Gain of disorder (P = 0.0019);Gain of disorder (P = 0.0019);
MVP		0.47
MPC		1.7
ClinPred		0.88	D
GERP RS		5.5
Varity_R		0.68
gMVP		0.87

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: chr3-58487328;