5-144474024-C-G

Variant names:

• chr5-144474024-C-G
• rs1199925227
• NM_020768.4:c.1197C>G

Variant summary

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

The NM_020768.4(KCTD16):​c.1197C>G​(p.Ile399Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,994 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)
• Consequence: KCTD16 NM_020768.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.92

Genes affected

KCTD16 (HGNC:29244): (potassium channel tetramerization domain containing 16) Predicted to be involved in protein homooligomerization. Predicted to act upstream of or within regulation of G protein-coupled receptor signaling pathway. Predicted to be located in cell projection. Predicted to be part of receptor complex. Predicted to be active in postsynaptic membrane and presynaptic membrane. [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 rank	MANE	Protein	UniProt
KCTD16	NM_020768.4	c.1197C>G	p.Ile399Met	missense_variant	Exon 4 of 4	ENST00000512467.6	NP_065819.1
KCTD16	NM_001370486.1	c.1197C>G	p.Ile399Met	missense_variant	Exon 3 of 3		NP_001357415.1
KCTD16	NM_001370487.1	c.1197C>G	p.Ile399Met	missense_variant	Exon 3 of 3		NP_001357416.1
KCTD16	XM_005268493.3	c.1197C>G	p.Ile399Met	missense_variant	Exon 3 of 3		XP_005268550.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCTD16	ENST00000512467.6	c.1197C>G	p.Ile399Met	missense_variant	Exon 4 of 4	1	NM_020768.4	ENSP00000424151.1
KCTD16	ENST00000507359.3	c.1197C>G	p.Ile399Met	missense_variant	Exon 3 of 3	1		ENSP00000426548.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151994 Hom.: 0 Cov.: 32

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 Cov.: 32

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151994 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74208

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

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1197C>G (p.I399M) alteration is located in exon 4 (coding exon 2) of the KCTD16 gene. This alteration results from a C to G substitution at nucleotide position 1197, causing the isoleucine (I) at amino acid position 399 to be replaced by a methionine (M). 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	Uncertain	0.55
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.41	N;N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.81
MutPred		0.18		Gain of ubiquitination at K404 (P = 0.0594);Gain of ubiquitination at K404 (P = 0.0594);
MVP		0.38
MPC		0.87
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.43
gMVP		0.58

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

Other links and lift over

dbSNP: rs1199925227; hg19: chr5-143853587;