chr1-111981693-C-A

Variant names:

• chr1-111981693-C-A
• rs797045634
• NM_001378969.1:c.1034G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001378969.1(KCND3):​c.1034G>T​(p.Gly345Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G345S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCND3 NM_001378969.1 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.17
• 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: 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001378969.1
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the KCND3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 20 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 3.8545 (above the threshold of 3.09). Trascript score misZ: 4.8782 (above the threshold of 3.09). GenCC associations: The gene is linked to spinocerebellar ataxia type 19/22, neurodevelopmental disorder, Brugada syndrome 1, Brugada syndrome 9.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 1-111981693-C-A is Pathogenic according to our data. Variant chr1-111981693-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 211216.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCND3	NM_001378969.1	c.1034G>T	p.Gly345Val	missense_variant	Exon 2 of 8	ENST00000302127.5	NP_001365898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCND3	ENST00000302127.5	c.1034G>T	p.Gly345Val	missense_variant	Exon 2 of 8	5	NM_001378969.1	ENSP00000306923.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spinocerebellar ataxia type 19/22 Pathogenic:1

Jun 27, 2014

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	M;M;M
PhyloP100		6.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Pathogenic	0.86
Sift	Benign	0.056	T;D;T
Sift4G	Benign	0.084	T;T;T
Polyphen		0.45	.;B;.
Vest4		0.98
MutPred		0.55		Loss of disorder (P = 0.036);Loss of disorder (P = 0.036);Loss of disorder (P = 0.036);
MVP		0.99
MPC		1.8
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.79
gMVP		0.99
Mutation Taster		=1/99	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: rs797045634; hg19: chr1-112524315; COSMIC: COSV104534002;