rs1373291

Variant names:

• chr1-111884229-G-T
• rs1373291
• NM_001378969.1:c.1107-97123C>A

Variant summary

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

The NM_001378969.1(KCND3):​c.1107-97123C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 152,100 control chromosomes in the GnomAD database, including 4,874 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 0.25 (4874 hom., cov: 32)
• Consequence: KCND3 NM_001378969.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0920
• Publications: 6 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCND3	NM_001378969.1	c.1107-97123C>A		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.1107-97123C>A		intron_variant	Intron 2 of 7	5	NM_001378969.1	ENSP00000306923.4

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37450 AN: 151980 Hom.: 4864 Cov.: 32

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.224

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

GnomAD4 genome AF: 0.247 AC: 37508 AN: 152100 Hom.: 4874 Cov.: 32 AF XY: 0.253 AC XY: 18800 AN XY: 74338

African (AFR) AF: 0.278 AC: 11520 AN: 41482

American (AMR) AF: 0.273 AC: 4182 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 596 AN: 3472

East Asian (EAS) AF: 0.438 AC: 2264 AN: 5168

South Asian (SAS) AF: 0.328 AC: 1581 AN: 4820

European-Finnish (FIN) AF: 0.301 AC: 3181 AN: 10556

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13566 AN: 68002

Other (OTH) AF: 0.230 AC: 483 AN: 2102

Alfa AF: 0.211 Hom.: 6032

Bravo AF: 0.248

Asia WGS AF: 0.392 AC: 1360 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	9.5
DANN	Benign	0.81
PhyloP100		-0.092
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: rs1373291; hg19: chr1-112426851;