chr1-111780417-ATT-A

Variant names:

• chr1-111780417-ATT-A
• rs72548727
• NM_001378969.1:c.1372-105_1372-104delAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001378969.1(KCND3):​c.1372-105_1372-104delAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,632 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCND3 NM_001378969.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.285
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCND3	NM_001378969.1	MANE Select	c.1372-105_1372-104delAA		intron	N/A	NP_001365898.1
	KCND3	NM_004980.5		c.1372-105_1372-104delAA		intron	N/A	NP_004971.2
	KCND3	NM_001378970.1		c.1372-105_1372-104delAA		intron	N/A	NP_001365899.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCND3	ENST00000302127.5	TSL:5 MANE Select	c.1372-105_1372-104delAA		intron	N/A	ENSP00000306923.4
	KCND3	ENST00000315987.6	TSL:1	c.1372-105_1372-104delAA		intron	N/A	ENSP00000319591.2
	KCND3	ENST00000369697.5	TSL:1	c.1372-105_1372-104delAA		intron	N/A	ENSP00000358711.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151632 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000481

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1019886 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 518644

African (AFR) AF: 0.00 AC: 0 AN: 23666

American (AMR) AF: 0.00 AC: 0 AN: 34104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22642

East Asian (EAS) AF: 0.00 AC: 0 AN: 33770

South Asian (SAS) AF: 0.00 AC: 0 AN: 70764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4350

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 737452

Other (OTH) AF: 0.00 AC: 0 AN: 44946

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151632 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74032

African (AFR) AF: 0.00 AC: 0 AN: 41282

American (AMR) AF: 0.00 AC: 0 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67876

Other (OTH) AF: 0.000481 AC: 1 AN: 2078

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.28

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: rs72548727; hg19: chr1-112323039;