rs2365669

Variant names:

• chr1-111820023-G-A
• rs2365669
• NM_001378969.1:c.1107-32917C>T

Variant summary

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

The NM_001378969.1(KCND3):​c.1107-32917C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 152,090 control chromosomes in the GnomAD database, including 21,542 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 0.49 (21542 hom., cov: 32)
• Consequence: KCND3 NM_001378969.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.562
• Publications: 7 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCND3	NM_001378969.1	c.1107-32917C>T		intron_variant	Intron 2 of 7	ENST00000302127.5	NP_001365898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCND3	ENST00000302127.5	c.1107-32917C>T		intron_variant	Intron 2 of 7	5	NM_001378969.1	ENSP00000306923.4
KCND3	ENST00000315987.6	c.1107-32917C>T		intron_variant	Intron 2 of 7	1		ENSP00000319591.2
KCND3	ENST00000369697.5	c.1107-32917C>T		intron_variant	Intron 1 of 5	1		ENSP00000358711.1

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74291 AN: 151972 Hom.: 21543 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.695

Gnomad AMR AF: 0.548

Gnomad ASJ AF: 0.666

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.574

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.580

Gnomad NFE AF: 0.631

Gnomad OTH AF: 0.526

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

GnomAD4 genome AF: 0.488 AC: 74285 AN: 152090 Hom.: 21542 Cov.: 32 AF XY: 0.493 AC XY: 36628 AN XY: 74356

African (AFR) AF: 0.165 AC: 6838 AN: 41488

American (AMR) AF: 0.548 AC: 8372 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 2311 AN: 3472

East Asian (EAS) AF: 0.330 AC: 1706 AN: 5176

South Asian (SAS) AF: 0.573 AC: 2762 AN: 4824

European-Finnish (FIN) AF: 0.707 AC: 7471 AN: 10564

Middle Eastern (MID) AF: 0.590 AC: 171 AN: 290

European-Non Finnish (NFE) AF: 0.631 AC: 42912 AN: 67968

Other (OTH) AF: 0.525 AC: 1108 AN: 2110

Alfa AF: 0.579 Hom.: 77037

Bravo AF: 0.462

Asia WGS AF: 0.475 AC: 1653 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.78
PhyloP100		-0.56
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: rs2365669; hg19: chr1-112362645; COSMIC: COSV56177485;