NM_001378969.1:c.264C>T

Variant names:

• chr1-111982463-G-A
• rs17221819
• NM_001378969.1:c.264C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378969.1(KCND3):​c.264C>T​(p.Pro88Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,612,354 control chromosomes in the GnomAD database, including 10,185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (618 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9567 hom.)
• Consequence: KCND3 NM_001378969.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.11
• Publications: 10 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-111982463-G-A is Benign according to our data. Variant chr1-111982463-G-A is described in ClinVar as Benign. ClinVar VariationId is 129314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.118 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.264C>T	p.Pro88Pro	synonymous	Exon 2 of 8	NP_001365898.1
	KCND3	NM_004980.5		c.264C>T	p.Pro88Pro	synonymous	Exon 2 of 8	NP_004971.2
	KCND3	NM_001378970.1		c.264C>T	p.Pro88Pro	synonymous	Exon 2 of 7	NP_001365899.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCND3	ENST00000302127.5	TSL:5 MANE Select	c.264C>T	p.Pro88Pro	synonymous	Exon 2 of 8	ENSP00000306923.4
	KCND3	ENST00000315987.6	TSL:1	c.264C>T	p.Pro88Pro	synonymous	Exon 2 of 8	ENSP00000319591.2
	KCND3	ENST00000369697.5	TSL:1	c.264C>T	p.Pro88Pro	synonymous	Exon 1 of 6	ENSP00000358711.1

Frequencies

GnomAD3 genomes AF: 0.0823 AC: 12522 AN: 152126 Hom.: 618 Cov.: 32

Gnomad AFR AF: 0.0460

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0630

Gnomad ASJ AF: 0.0734

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0561

Gnomad FIN AF: 0.0646

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.0727

GnomAD2 exomes AF: 0.0842 AC: 21137 AN: 251016 AF XY: 0.0866

Gnomad AFR exome AF: 0.0463

Gnomad AMR exome AF: 0.0415

Gnomad ASJ exome AF: 0.0738

Gnomad EAS exome AF: 0.000870

Gnomad FIN exome AF: 0.0660

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.0871

GnomAD4 exome AF: 0.109 AC: 159107 AN: 1460110 Hom.: 9567 Cov.: 33 AF XY: 0.108 AC XY: 78351 AN XY: 725930

African (AFR) AF: 0.0423 AC: 1413 AN: 33438

American (AMR) AF: 0.0442 AC: 1974 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0762 AC: 1987 AN: 26088

East Asian (EAS) AF: 0.000883 AC: 35 AN: 39636

South Asian (SAS) AF: 0.0645 AC: 5557 AN: 86214

European-Finnish (FIN) AF: 0.0698 AC: 3729 AN: 53390

Middle Eastern (MID) AF: 0.0746 AC: 430 AN: 5766

European-Non Finnish (NFE) AF: 0.125 AC: 138278 AN: 1110584

Other (OTH) AF: 0.0946 AC: 5704 AN: 60294

GnomAD4 genome AF: 0.0822 AC: 12522 AN: 152244 Hom.: 618 Cov.: 32 AF XY: 0.0792 AC XY: 5891 AN XY: 74416

African (AFR) AF: 0.0459 AC: 1906 AN: 41562

American (AMR) AF: 0.0629 AC: 962 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0734 AC: 255 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5166

South Asian (SAS) AF: 0.0557 AC: 268 AN: 4812

European-Finnish (FIN) AF: 0.0646 AC: 685 AN: 10608

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8176 AN: 68006

Other (OTH) AF: 0.0724 AC: 153 AN: 2114

Alfa AF: 0.103 Hom.: 792

Bravo AF: 0.0813

Asia WGS AF: 0.0260 AC: 91 AN: 3478

EpiCase AF: 0.115

EpiControl AF: 0.123

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 23, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 28, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Apr 05, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Cardiovascular phenotype Benign:1

Jun 18, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Spinocerebellar ataxia type 19/22 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.9
DANN	Benign	0.85
PhyloP100		-3.1
PromoterAI		0.0087	Neutral
Mutation Taster		=98/2	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: rs17221819; hg19: chr1-112525085; COSMIC: COSV56190733;