1-111982352-C-T

Variant names:

• chr1-111982352-C-T
• rs2289723
• NM_001378969.1:c.375G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378969.1(KCND3):​c.375G>A​(p.Pro125Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00964 in 1,614,078 control chromosomes in the GnomAD database, including 581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P125P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (97 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (484 hom.)
• Consequence: KCND3 NM_001378969.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.67
• Publications: 5 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 1-111982352-C-T is Benign according to our data. Variant chr1-111982352-C-T is described in ClinVar as Benign. ClinVar VariationId is 380951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.67 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0891 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378969.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCND3	NM_001378969.1	MANE Select	c.375G>A	p.Pro125Pro	synonymous	Exon 2 of 8	NP_001365898.1	Q9UK17-1
	KCND3	NM_004980.5		c.375G>A	p.Pro125Pro	synonymous	Exon 2 of 8	NP_004971.2
	KCND3	NM_001378970.1		c.375G>A	p.Pro125Pro	synonymous	Exon 2 of 7	NP_001365899.1	Q9UK17-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCND3	ENST00000302127.5	TSL:5 MANE Select	c.375G>A	p.Pro125Pro	synonymous	Exon 2 of 8	ENSP00000306923.4	Q9UK17-1
	KCND3	ENST00000315987.6	TSL:1	c.375G>A	p.Pro125Pro	synonymous	Exon 2 of 8	ENSP00000319591.2	Q9UK17-1
	KCND3	ENST00000369697.5	TSL:1	c.375G>A	p.Pro125Pro	synonymous	Exon 1 of 6	ENSP00000358711.1	Q9UK17-2

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3511 AN: 152080 Hom.: 97 Cov.: 32

Gnomad AFR AF: 0.0607

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.0960

Gnomad SAS AF: 0.0210

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0186 AC: 4681 AN: 251386 AF XY: 0.0163

Gnomad AFR exome AF: 0.0616

Gnomad AMR exome AF: 0.0277

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.100

Gnomad FIN exome AF: 0.00277

Gnomad NFE exome AF: 0.000985

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00824 AC: 12044 AN: 1461880 Hom.: 484 Cov.: 32 AF XY: 0.00831 AC XY: 6045 AN XY: 727246

African (AFR) AF: 0.0645 AC: 2159 AN: 33480

American (AMR) AF: 0.0251 AC: 1123 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26136

East Asian (EAS) AF: 0.129 AC: 5130 AN: 39700

South Asian (SAS) AF: 0.0193 AC: 1661 AN: 86258

European-Finnish (FIN) AF: 0.00285 AC: 152 AN: 53406

Middle Eastern (MID) AF: 0.0114 AC: 66 AN: 5768

European-Non Finnish (NFE) AF: 0.000847 AC: 942 AN: 1112012

Other (OTH) AF: 0.0132 AC: 796 AN: 60396

GnomAD4 genome AF: 0.0231 AC: 3521 AN: 152198 Hom.: 97 Cov.: 32 AF XY: 0.0232 AC XY: 1726 AN XY: 74408

African (AFR) AF: 0.0607 AC: 2521 AN: 41520

American (AMR) AF: 0.0160 AC: 244 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.0961 AC: 495 AN: 5152

South Asian (SAS) AF: 0.0206 AC: 99 AN: 4810

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00118 AC: 80 AN: 68018

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.00930 Hom.: 54

Bravo AF: 0.0266

Asia WGS AF: 0.0570 AC: 199 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00148

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)
-	-	1	Spinocerebellar ataxia type 19/22 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.1
DANN	Benign	0.89
PhyloP100		-1.7
PromoterAI		0.0054	Neutral
Mutation Taster		=99/1	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: rs2289723; hg19: chr1-112524974; COSMIC: COSV56181318;