rs640029

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0600

Publications

8 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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
KCND3NM_001378969.1 linkc.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
KCND3ENST00000302127.5 linkc.1518+26A>T intron_variant Intron 6 of 7 5 NM_001378969.1 ENSP00000306923.4 Q9UK17-1
KCND3ENST00000315987.6 linkc.1518+26A>T intron_variant Intron 6 of 7 1 ENSP00000319591.2 Q9UK17-1
KCND3ENST00000369697.5 linkc.1462-1137A>T intron_variant Intron 4 of 5 1 ENSP00000358711.1 Q9UK17-2
KCND3ENST00000703640.1 linkn.2153-1137A>T intron_variant Intron 2 of 2

Frequencies

GnomAD3 genomes
AF:
0.224
AC:
33961
AN:
151808
Hom.:
4246
Cov.:
31
show subpopulations
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
show subpopulations
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
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.478
Heterozygous variant carriers
0
10422
20845
31267
41690
52112
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
7672
15344
23016
30688
38360
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.224
AC:
34000
AN:
151926
Hom.:
4250
Cov.:
31
AF XY:
0.219
AC XY:
16258
AN XY:
74266
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
1322
2643
3965
5286
6608
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
336
672
1008
1344
1680
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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
LINK: link

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

Publications

Other links and lift over

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