1-111921754-C-T

Variant names:

• chr1-111921754-C-T
• rs17029069
• NM_001378969.1:c.1106+59867G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378969.1(KCND3):​c.1106+59867G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 151,986 control chromosomes in the GnomAD database, including 5,597 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (5597 hom., cov: 32)
• Consequence: KCND3 NM_001378969.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.250
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCND3	NM_001378969.1	MANE Select	c.1106+59867G>A		intron	N/A	NP_001365898.1
	KCND3	NM_004980.5		c.1106+59867G>A		intron	N/A	NP_004971.2
	KCND3	NM_001378970.1		c.1106+59867G>A		intron	N/A	NP_001365899.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCND3	ENST00000302127.5	TSL:5 MANE Select	c.1106+59867G>A		intron	N/A	ENSP00000306923.4
	KCND3	ENST00000315987.6	TSL:1	c.1106+59867G>A		intron	N/A	ENSP00000319591.2
	KCND3	ENST00000369697.5	TSL:1	c.1106+59867G>A		intron	N/A	ENSP00000358711.1

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39259 AN: 151868 Hom.: 5591 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.291

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.258 AC: 39284 AN: 151986 Hom.: 5597 Cov.: 32 AF XY: 0.261 AC XY: 19425 AN XY: 74296

African (AFR) AF: 0.134 AC: 5540 AN: 41452

American (AMR) AF: 0.305 AC: 4665 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1118 AN: 3470

East Asian (EAS) AF: 0.481 AC: 2472 AN: 5136

South Asian (SAS) AF: 0.278 AC: 1340 AN: 4812

European-Finnish (FIN) AF: 0.289 AC: 3050 AN: 10558

Middle Eastern (MID) AF: 0.257 AC: 75 AN: 292

European-Non Finnish (NFE) AF: 0.296 AC: 20091 AN: 67966

Other (OTH) AF: 0.292 AC: 615 AN: 2108

Alfa AF: 0.288 Hom.: 25552

Bravo AF: 0.257

Asia WGS AF: 0.344 AC: 1193 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.4
DANN	Benign	0.62
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

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: rs17029069; hg19: chr1-112464376;