rs640029

Positions:

• chr1-111778410-T-A

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.1518+26A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,598,466 control chromosomes in the GnomAD database, including 33,181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4250 hom., cov: 31)
  • Exomes 𝑓: 0.19 (28931 hom.)
• Consequence: KCND3 NM_001378969.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0600

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=-0.53).
• BP6: Variant 1-111778410-T-A is Benign according to our data. Variant chr1-111778410-T-A is described in ClinVar as [Benign]. Clinvar id is 1293604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCND3	NM_001378969.1	c.1518+26A>T		intron_variant		ENST00000302127.5	NP_001365898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCND3	ENST00000302127.5	c.1518+26A>T		intron_variant		5	NM_001378969.1	ENSP00000306923	P3
KCND3	ENST00000315987.6	c.1518+26A>T		intron_variant		1		ENSP00000319591	P3
KCND3	ENST00000369697.5	c.1462-1137A>T		intron_variant		1		ENSP00000358711	A1
KCND3	ENST00000703640.1	n.2153-1137A>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.224 AC: 33961 AN: 151808 Hom.: 4246 Cov.: 31

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.0400

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.212

GnomAD3 exomes AF: 0.173 AC: 43512 AN: 251144 Hom.: 4464 AF XY: 0.173 AC XY: 23482 AN XY: 135762

Gnomad AFR exome AF: 0.343

Gnomad AMR exome AF: 0.0847

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.0407

Gnomad SAS exome AF: 0.147

Gnomad FIN exome AF: 0.225

Gnomad NFE exome AF: 0.198

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.193 AC: 279882 AN: 1446540 Hom.: 28931 Cov.: 29 AF XY: 0.192 AC XY: 138378 AN XY: 720660

Gnomad4 AFR exome AF: 0.346

Gnomad4 AMR exome AF: 0.0911

Gnomad4 ASJ exome AF: 0.133

Gnomad4 EAS exome AF: 0.0312

Gnomad4 SAS exome AF: 0.145

Gnomad4 FIN exome AF: 0.229

Gnomad4 NFE exome AF: 0.203

Gnomad4 OTH exome AF: 0.181

GnomAD4 genome AF: 0.224 AC: 34000 AN: 151926 Hom.: 4250 Cov.: 31 AF XY: 0.219 AC XY: 16258 AN XY: 74266

Gnomad4 AFR AF: 0.337

Gnomad4 AMR AF: 0.143

Gnomad4 ASJ AF: 0.137

Gnomad4 EAS AF: 0.0399

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.220

Gnomad4 NFE AF: 0.199

Gnomad4 OTH AF: 0.215

Alfa AF: 0.201 Hom.: 592

Bravo AF: 0.223

Asia WGS AF: 0.103 AC: 358 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs640029; hg19: chr1-112321032;