rs3738298

chr1-111786929-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378969.1(KCND3):c.1269+15C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,558 control chromosomes in the GnomAD database, including 19,222 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2121 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17101 hom.)
• Consequence: KCND3 NM_001378969.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.440

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-111786929-G-T is Benign according to our data. Variant chr1-111786929-G-T is described in ClinVar as [Benign]. Clinvar id is 259600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-111786929-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCND3	NM_001378969.1	c.1269+15C>A		intron_variant		ENST00000302127.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCND3	ENST00000302127.5	c.1269+15C>A		intron_variant		5	NM_001378969.1	P3
KCND3	ENST00000315987.6	c.1269+15C>A		intron_variant		1		P3
KCND3	ENST00000369697.5	c.1269+15C>A		intron_variant		1		A1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25253 AN: 152000 Hom.: 2119 Cov.: 32

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.158

GnomAD3 exomes AF: 0.162 AC: 40826 AN: 251250 Hom.: 3478 AF XY: 0.166 AC XY: 22583 AN XY: 135826

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.204

Gnomad SAS exome AF: 0.215

Gnomad FIN exome AF: 0.197

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.150 AC: 219214 AN: 1461440 Hom.: 17101 Cov.: 33 AF XY: 0.152 AC XY: 110725 AN XY: 727032

Gnomad4 AFR exome AF: 0.195

Gnomad4 AMR exome AF: 0.115

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.213

Gnomad4 SAS exome AF: 0.215

Gnomad4 FIN exome AF: 0.198

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.166 AC: 25258 AN: 152118 Hom.: 2121 Cov.: 32 AF XY: 0.170 AC XY: 12671 AN XY: 74368

Gnomad4 AFR AF: 0.190

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.150

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.212

Gnomad4 FIN AF: 0.200

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.158

Alfa AF: 0.148 Hom.: 3606

Bravo AF: 0.158

Asia WGS AF: 0.204 AC: 713 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Spinocerebellar ataxia type 19/22 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	2.3
Dann	Benign	0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs3738298; hg19: chr1-112329551; COSMIC: COSV56180805;