KCND3 p.Thr486Ala

Variant names:

• chr1-111780230-T-C
• rs149008060
• NM_001378969.1:c.1456A>G
• KCND3 p.Thr486Ala

Your query was ambiguous. Multiple possible variants found:

• chr1-111780230-T-C
• chr1-111780228-GGT-AGC
• chr1-111780228-GGT-TGC
• chr1-111780228-GGT-CGC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_001378969.1(KCND3):​c.1456A>G​(p.Thr486Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,584,728 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T486T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00075 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: KCND3 NM_001378969.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 7.42
• Publications: 8 publications found

Genes affected

KCND3 (HGNC:6239): (potassium voltage-gated channel subfamily D member 3) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shal-related subfamily, members of which form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential. This member includes two isoforms with different sizes, which are encoded by alternatively spliced transcript variants of this gene. [provided by RefSeq, Jul 2008]

KCND3 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: G2P
• spinocerebellar ataxia type 19/22

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• Brugada syndrome 9

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• PP2: Missense variant in the KCND3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 20 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 3.8545 (above the threshold of 3.09). Trascript score misZ: 4.8782 (above the threshold of 3.09). GenCC associations: The gene is linked to spinocerebellar ataxia type 19/22, Brugada syndrome 9, Brugada syndrome 1, neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.060301185).
• BP6: Variant 1-111780230-T-C is Benign according to our data. Variant chr1-111780230-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 415286.
• BS2: High AC in GnomAd4 at 114 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378969.1. 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
	KCND3	NM_001378969.1	MANE Select	c.1456A>G	p.Thr486Ala	missense	Exon 5 of 8	NP_001365898.1	Q9UK17-1
	KCND3	NM_004980.5		c.1456A>G	p.Thr486Ala	missense	Exon 5 of 8	NP_004971.2
	KCND3	NM_001378970.1		c.1456A>G	p.Thr486Ala	missense	Exon 5 of 7	NP_001365899.1	Q9UK17-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCND3	ENST00000302127.5	TSL:5 MANE Select	c.1456A>G	p.Thr486Ala	missense	Exon 5 of 8	ENSP00000306923.4	Q9UK17-1
	KCND3	ENST00000315987.6	TSL:1	c.1456A>G	p.Thr486Ala	missense	Exon 5 of 8	ENSP00000319591.2	Q9UK17-1
	KCND3	ENST00000369697.5	TSL:1	c.1456A>G	p.Thr486Ala	missense	Exon 4 of 6	ENSP00000358711.1	Q9UK17-2

Frequencies

GnomAD3 genomes AF: 0.000751 AC: 114 AN: 151898 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.000612 AC: 126 AN: 206024 AF XY: 0.000648

Gnomad AFR exome AF: 0.000159

Gnomad AMR exome AF: 0.000167

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000112

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.000939

GnomAD4 exome AF: 0.00109 AC: 1557 AN: 1432712 Hom.: 1 Cov.: 32 AF XY: 0.00110 AC XY: 778 AN XY: 709168

African (AFR) AF: 0.000151 AC: 5 AN: 33086

American (AMR) AF: 0.000222 AC: 9 AN: 40626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25498

East Asian (EAS) AF: 0.00 AC: 0 AN: 38844

South Asian (SAS) AF: 0.000233 AC: 19 AN: 81618

European-Finnish (FIN) AF: 0.000213 AC: 11 AN: 51564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5350

European-Non Finnish (NFE) AF: 0.00132 AC: 1450 AN: 1096726

Other (OTH) AF: 0.00106 AC: 63 AN: 59400

GnomAD4 genome AF: 0.000750 AC: 114 AN: 152016 Hom.: 1 Cov.: 32 AF XY: 0.000673 AC XY: 50 AN XY: 74292

African (AFR) AF: 0.000386 AC: 16 AN: 41480

American (AMR) AF: 0.000197 AC: 3 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4802

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10578

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

European-Non Finnish (NFE) AF: 0.00134 AC: 91 AN: 67966

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.000991 Hom.: 1

Bravo AF: 0.000740

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	1	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	KCND3-related disorder (1)
-	-	1	Spinocerebellar ataxia type 19/22 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.060	T
MetaSVM	Uncertain	0.084	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.65
Sift	Benign	0.18	T
Sift4G	Benign	0.13	T
Varity_R		0.32
gMVP		0.67
Mutation Taster		=88/12	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs149008060; hg19: chr1-112322852;