rs930548

Variant names:

• chr1-111964942-C-G
• rs930548
• NM_001378969.1:c.1106+16679G>C

Variant summary

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

The NM_001378969.1(KCND3):​c.1106+16679G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 151,936 control chromosomes in the GnomAD database, including 12,988 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 0.41 (12988 hom., cov: 31)
• Consequence: KCND3 NM_001378969.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.289
• Publications: 3 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCND3	NM_001378969.1	c.1106+16679G>C		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.1106+16679G>C		intron_variant	Intron 2 of 7	5	NM_001378969.1	ENSP00000306923.4

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62061 AN: 151820 Hom.: 12976 Cov.: 31

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.443

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.408

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

GnomAD4 genome AF: 0.409 AC: 62111 AN: 151936 Hom.: 12988 Cov.: 31 AF XY: 0.401 AC XY: 29767 AN XY: 74258

African (AFR) AF: 0.404 AC: 16734 AN: 41404

American (AMR) AF: 0.318 AC: 4856 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 1537 AN: 3468

East Asian (EAS) AF: 0.247 AC: 1276 AN: 5164

South Asian (SAS) AF: 0.401 AC: 1928 AN: 4806

European-Finnish (FIN) AF: 0.338 AC: 3567 AN: 10546

Middle Eastern (MID) AF: 0.466 AC: 136 AN: 292

European-Non Finnish (NFE) AF: 0.453 AC: 30756 AN: 67948

Other (OTH) AF: 0.409 AC: 864 AN: 2114

Alfa AF: 0.421 Hom.: 1641

Bravo AF: 0.406

Asia WGS AF: 0.331 AC: 1155 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.4
DANN	Benign	0.67
PhyloP100		0.29
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: rs930548; hg19: chr1-112507564;