8-25432514-G-T

Position:

• chr8-25432514-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000221200.9(KCTD9):​c.1043C>A​(p.Thr348Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCTD9 ENST00000221200.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

Genes affected

KCTD9 (HGNC:22401): (potassium channel tetramerization domain containing 9) Enables cullin family protein binding activity; identical protein binding activity; and protein self-association. Predicted to be involved in intracellular signal transduction; protein homooligomerization; and protein ubiquitination. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCTD9	NM_017634.4	c.1043C>A	p.Thr348Asn	missense_variant	11/12	ENST00000221200.9	NP_060104.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCTD9	ENST00000221200.9	c.1043C>A	p.Thr348Asn	missense_variant	11/12	1	NM_017634.4	ENSP00000221200.4
KCTD9	ENST00000710397.1	c.1163C>A	p.Thr388Asn	missense_variant	11/12			ENSP00000518251.1
KCTD9	ENST00000519665.5	n.*1002C>A		non_coding_transcript_exon_variant	10/11	5		ENSP00000466874.1
KCTD9	ENST00000519665.5	n.*1002C>A		3_prime_UTR_variant	10/11	5		ENSP00000466874.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Jun 17, 2024

The c.1043C>A (p.T348N) alteration is located in exon 11 (coding exon 11) of the KCTD9 gene. This alteration results from a C to A substitution at nucleotide position 1043, causing the threonine (T) at amino acid position 348 to be replaced by an asparagine (N). 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	0.99
BayesDel_addAF	Benign	-0.0095	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.82
MutPred		0.79		Gain of disorder (P = 0.1114);
MVP		0.75
MPC		2.2
ClinPred		0.91	D
GERP RS		5.4
Varity_R		0.46
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr8-25290030;