NM_001378969.1:c.1518+26A>T

Variant names:

• chr1-111778410-T-A
• rs640029
• NM_001378969.1:c.1518+26A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378969.1(KCND3):​c.1518+26A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,598,466 control chromosomes in the GnomAD database, including 33,181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4250 hom., cov: 31)
  • Exomes 𝑓: 0.19 (28931 hom.)
• Consequence: KCND3 NM_001378969.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0600
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-111778410-T-A is Benign according to our data. Variant chr1-111778410-T-A is described in ClinVar as [Benign]. Clinvar id is 1293604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCND3	NM_001378969.1	c.1518+26A>T		intron_variant	Intron 6 of 7	ENST00000302127.5	NP_001365898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCND3	ENST00000302127.5	c.1518+26A>T		intron_variant	Intron 6 of 7	5	NM_001378969.1	ENSP00000306923.4
KCND3	ENST00000315987.6	c.1518+26A>T		intron_variant	Intron 6 of 7	1		ENSP00000319591.2
KCND3	ENST00000369697.5	c.1462-1137A>T		intron_variant	Intron 4 of 5	1		ENSP00000358711.1
KCND3	ENST00000703640.1	n.2153-1137A>T		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.224 AC: 33961 AN: 151808 Hom.: 4246 Cov.: 31

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.0400

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.212

GnomAD2 exomes AF: 0.173 AC: 43512 AN: 251144 AF XY: 0.173

Gnomad AFR exome AF: 0.343

Gnomad AMR exome AF: 0.0847

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.0407

Gnomad FIN exome AF: 0.225

Gnomad NFE exome AF: 0.198

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.193 AC: 279882 AN: 1446540 Hom.: 28931 Cov.: 29 AF XY: 0.192 AC XY: 138378 AN XY: 720660

African (AFR) AF: 0.346 AC: 11481 AN: 33140

American (AMR) AF: 0.0911 AC: 4072 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3455 AN: 26042

East Asian (EAS) AF: 0.0312 AC: 1238 AN: 39636

South Asian (SAS) AF: 0.145 AC: 12440 AN: 85990

European-Finnish (FIN) AF: 0.229 AC: 12250 AN: 53398

Middle Eastern (MID) AF: 0.153 AC: 878 AN: 5736

European-Non Finnish (NFE) AF: 0.203 AC: 223231 AN: 1098088

Other (OTH) AF: 0.181 AC: 10837 AN: 59812

GnomAD4 genome AF: 0.224 AC: 34000 AN: 151926 Hom.: 4250 Cov.: 31 AF XY: 0.219 AC XY: 16258 AN XY: 74266

African (AFR) AF: 0.337 AC: 13929 AN: 41352

American (AMR) AF: 0.143 AC: 2179 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 473 AN: 3464

East Asian (EAS) AF: 0.0399 AC: 207 AN: 5182

South Asian (SAS) AF: 0.140 AC: 675 AN: 4826

European-Finnish (FIN) AF: 0.220 AC: 2321 AN: 10544

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13554 AN: 67958

Other (OTH) AF: 0.215 AC: 453 AN: 2110

Alfa AF: 0.201 Hom.: 592

Bravo AF: 0.223

Asia WGS AF: 0.103 AC: 358 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.65
PhyloP100		0.060
Mutation Taster		=100/0	polymorphism (auto)

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: rs640029; hg19: chr1-112321032; COSMIC: COSV107332802;