1-111873000-T-C

Variant names:

• chr1-111873000-T-C
• rs2618034
• NM_001378969.1:c.1107-85894A>G

Variant summary

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

The NM_001378969.1(KCND3):​c.1107-85894A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 152,210 control chromosomes in the GnomAD database, including 3,581 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 0.19 (3581 hom., cov: 33)
• Consequence: KCND3 NM_001378969.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0230
• Publications: 4 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCND3	NM_001378969.1	c.1107-85894A>G		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.1107-85894A>G		intron_variant	Intron 2 of 7	5	NM_001378969.1	ENSP00000306923.4

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28129 AN: 152092 Hom.: 3570 Cov.: 33

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.0891

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0878

Gnomad OTH AF: 0.174

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

GnomAD4 genome AF: 0.185 AC: 28181 AN: 152210 Hom.: 3581 Cov.: 33 AF XY: 0.195 AC XY: 14478 AN XY: 74424

African (AFR) AF: 0.293 AC: 12175 AN: 41518

American (AMR) AF: 0.222 AC: 3401 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0891 AC: 309 AN: 3468

East Asian (EAS) AF: 0.533 AC: 2755 AN: 5170

South Asian (SAS) AF: 0.238 AC: 1147 AN: 4828

European-Finnish (FIN) AF: 0.188 AC: 1991 AN: 10598

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0878 AC: 5971 AN: 68016

Other (OTH) AF: 0.176 AC: 370 AN: 2106

Alfa AF: 0.147 Hom.: 277

Bravo AF: 0.194

Asia WGS AF: 0.400 AC: 1387 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.7
DANN	Benign	0.86
PhyloP100		0.023
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: rs2618034; hg19: chr1-112415622;