1-111791852-T-C

Variant names:

• chr1-111791852-T-C
• rs1246194
• NM_001378969.1:c.1107-4746A>G

Variant summary

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

The NM_001378969.1(KCND3):​c.1107-4746A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.692 in 152,132 control chromosomes in the GnomAD database, including 36,958 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 0.69 (36958 hom., cov: 32)
• Consequence: KCND3 NM_001378969.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.336
• 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

LOC124904312 (HGNC:):

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 = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCND3	NM_001378969.1	c.1107-4746A>G		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.1107-4746A>G		intron_variant	Intron 2 of 7	5	NM_001378969.1	ENSP00000306923.4
KCND3	ENST00000315987.6	c.1107-4746A>G		intron_variant	Intron 2 of 7	1		ENSP00000319591.2
KCND3	ENST00000369697.5	c.1107-4746A>G		intron_variant	Intron 1 of 5	1		ENSP00000358711.1

Frequencies

GnomAD3 genomes AF: 0.692 AC: 105124 AN: 152014 Hom.: 36930 Cov.: 32

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.663

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.717

Gnomad EAS AF: 0.832

Gnomad SAS AF: 0.818

Gnomad FIN AF: 0.803

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.732

Gnomad OTH AF: 0.700

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

GnomAD4 genome AF: 0.692 AC: 105203 AN: 152132 Hom.: 36958 Cov.: 32 AF XY: 0.697 AC XY: 51833 AN XY: 74382

African (AFR) AF: 0.560 AC: 23231 AN: 41458

American (AMR) AF: 0.695 AC: 10638 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.717 AC: 2491 AN: 3472

East Asian (EAS) AF: 0.831 AC: 4303 AN: 5176

South Asian (SAS) AF: 0.818 AC: 3940 AN: 4818

European-Finnish (FIN) AF: 0.803 AC: 8503 AN: 10592

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.732 AC: 49808 AN: 68000

Other (OTH) AF: 0.705 AC: 1488 AN: 2112

Alfa AF: 0.717 Hom.: 62500

Bravo AF: 0.675

Asia WGS AF: 0.803 AC: 2790 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	9.3
DANN	Benign	0.64
PhyloP100		0.34
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: rs1246194; hg19: chr1-112334474;