rs12720446

Variant names:

• chr1-111982610-A-G
• rs12720446
• NM_001378969.1:c.117T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001378969.1(KCND3):​c.117T>C​(p.Asp39Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,611,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: KCND3 NM_001378969.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.599
• Publications: 1 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 1-111982610-A-G is Benign according to our data. Variant chr1-111982610-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 415284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.599 with no splicing effect.
• BS2: High AC in GnomAd4 at 183 AD gene.

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.117T>C	p.Asp39Asp	synonymous	Exon 2 of 8	NP_001365898.1	Q9UK17-1
	KCND3	NM_004980.5		c.117T>C	p.Asp39Asp	synonymous	Exon 2 of 8	NP_004971.2
	KCND3	NM_001378970.1		c.117T>C	p.Asp39Asp	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.117T>C	p.Asp39Asp	synonymous	Exon 2 of 8	ENSP00000306923.4	Q9UK17-1
	KCND3	ENST00000315987.6	TSL:1	c.117T>C	p.Asp39Asp	synonymous	Exon 2 of 8	ENSP00000319591.2	Q9UK17-1
	KCND3	ENST00000369697.5	TSL:1	c.117T>C	p.Asp39Asp	synonymous	Exon 1 of 6	ENSP00000358711.1	Q9UK17-2

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000327 AC: 82 AN: 251146 AF XY: 0.000228

Gnomad AFR exome AF: 0.00425

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000112 AC: 164 AN: 1459556 Hom.: 0 Cov.: 32 AF XY: 0.0000923 AC XY: 67 AN XY: 726030

African (AFR) AF: 0.00395 AC: 132 AN: 33448

American (AMR) AF: 0.000201 AC: 9 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109974

Other (OTH) AF: 0.000282 AC: 17 AN: 60320

GnomAD4 genome AF: 0.00120 AC: 183 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74432

African (AFR) AF: 0.00429 AC: 178 AN: 41532

American (AMR) AF: 0.000131 AC: 2 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000736 Hom.: 0

Bravo AF: 0.00153

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not specified (1)
-	-	1	Spinocerebellar ataxia type 19/22 (1)
-	-	1	Spinocerebellar ataxia type 19/22;C4225340:Brugada syndrome 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.2
DANN	Benign	0.57
PhyloP100		0.60
PromoterAI		-0.023	Neutral
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs12720446; hg19: chr1-112525232;