1-215579093-C-T

Variant names:

• chr1-215579093-C-T
• rs146224994
• NM_016121.5:c.491C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_016121.5(KCTD3):​c.491C>T​(p.Thr164Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,607,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: KCTD3 NM_016121.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27
• Publications: 2 publications found

Genes affected

KCTD3 (HGNC:21305): (potassium channel tetramerization domain containing 3) This gene encodes a member of the potassium channel tetramerization-domain containing (KCTD) protein family. Members of this protein family regulate the biophysical characteristics of ion channels. In mouse, this protein interacts with hyperpolarization-activated cyclic nucleotide-gated channel complex 3 and enhances its cell surface expression and current density. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024865419).
• BS2: High AC in GnomAd4 at 33 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016121.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCTD3	NM_016121.5	MANE Select	c.491C>T	p.Thr164Ile	missense	Exon 7 of 18	NP_057205.2
	KCTD3	NM_001319294.2		c.491C>T	p.Thr164Ile	missense	Exon 7 of 18	NP_001306223.1	Q9Y597-2
	KCTD3	NM_001319295.2		c.185C>T	p.Thr62Ile	missense	Exon 7 of 18	NP_001306224.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCTD3	ENST00000259154.9	TSL:1 MANE Select	c.491C>T	p.Thr164Ile	missense	Exon 7 of 18	ENSP00000259154.2	Q9Y597-1
	KCTD3	ENST00000964520.1		c.512C>T	p.Thr171Ile	missense	Exon 7 of 18	ENSP00000634579.1
	KCTD3	ENST00000964519.1		c.491C>T	p.Thr164Ile	missense	Exon 8 of 19	ENSP00000634578.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000490 AC: 12 AN: 244910 AF XY: 0.0000151

Gnomad AFR exome AF: 0.000506

Gnomad AMR exome AF: 0.0000603

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1454744 Hom.: 0 Cov.: 29 AF XY: 0.00000967 AC XY: 7 AN XY: 723652

African (AFR) AF: 0.000396 AC: 13 AN: 32794

American (AMR) AF: 0.0000696 AC: 3 AN: 43108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.00 AC: 0 AN: 39258

South Asian (SAS) AF: 0.0000236 AC: 2 AN: 84884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109526

Other (OTH) AF: 0.0000333 AC: 2 AN: 60098

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74464

African (AFR) AF: 0.000746 AC: 31 AN: 41546

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000803 Hom.: 0

Bravo AF: 0.000200

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.040
Sift	Benign	0.27	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.080
MVP		0.21
MPC		0.85
ClinPred		0.019	T
GERP RS		4.8
Varity_R		0.041
gMVP		0.30
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs146224994; hg19: chr1-215752436;