rs397515475

Variant names:

• chr1-111982044-CAGA-C
• rs397515475
• NM_001378969.1:c.680_682delTCT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_001378969.1(KCND3):​c.680_682delTCT​(p.Phe227del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F227F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KCND3 NM_001378969.1 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.32
• Publications: 9 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: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001378969.1. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-111982044-CAGA-C is Pathogenic according to our data. Variant chr1-111982044-CAGA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 66061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.680_682delTCT	p.Phe227del	disruptive_inframe_deletion	Exon 2 of 8	NP_001365898.1	Q9UK17-1
	KCND3	NM_004980.5		c.680_682delTCT	p.Phe227del	disruptive_inframe_deletion	Exon 2 of 8	NP_004971.2
	KCND3	NM_001378970.1		c.680_682delTCT	p.Phe227del	disruptive_inframe_deletion	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.680_682delTCT	p.Phe227del	disruptive_inframe_deletion	Exon 2 of 8	ENSP00000306923.4	Q9UK17-1
	KCND3	ENST00000315987.6	TSL:1	c.680_682delTCT	p.Phe227del	disruptive_inframe_deletion	Exon 2 of 8	ENSP00000319591.2	Q9UK17-1
	KCND3	ENST00000369697.5	TSL:1	c.680_682delTCT	p.Phe227del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000358711.1	Q9UK17-2

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Spinocerebellar ataxia type 19/22 (3)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=19/81	disease causing (ClinVar)

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: rs397515475; hg19: chr1-112524666; COSMIC: COSV56184108;