dbSNP rs143686945: KCND1:p.Lys353Glu (chrX-48969215-T-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_004979.6(KCND1):c.1057A>G(p.Lys353Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,208,595 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 62 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.00016 ( 0 hom. 57 hem. )

Consequence

KCND1
NM_004979.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.73

Publications

0 publications found

Variant links:

Genes affected

KCND1 (HGNC:6237): (potassium voltage-gated channel subfamily D member 1) This gene encodes a multipass membrane protein that comprises the pore subunit of the voltage-gated A-type potassium channel, which functions in the repolarization of membrane action potentials. Activity of voltage-gated potassium channels is important in a number of physiological processes, among them the regulation of neurotransmitter release, heart rate, insulin secretion, and smooth muscle contraction. [provided by RefSeq, Aug 2013]

KCND1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009565294).

BS2

High Hemizygotes in GnomAd4 at 5 geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004979.6. 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
	KCND1	NM_004979.6	MANE Select	c.1057A>G	p.Lys353Glu	missense	Exon 1 of 6	NP_004970.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCND1	ENST00000218176.4	TSL:1 MANE Select	c.1057A>G	p.Lys353Glu	missense	Exon 1 of 6	ENSP00000218176.3	Q9NSA2-1
KCND1	ENST00000935975.1		c.1057A>G	p.Lys353Glu	missense	Exon 1 of 6	ENSP00000606034.1
KCND1	ENST00000935976.1		c.1057A>G	p.Lys353Glu	missense	Exon 1 of 6	ENSP00000606035.1

Frequencies

GnomAD3 genomes

AF:

0.000143

AC:

AN:

111505

Hom.:

Cov.:

show subpopulations

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:

0.00216

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000566

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000261

AC:

AN:

179922

AF XY:

0.000232

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00221

Gnomad NFE exome

AF:

0.000112

Gnomad OTH exome

AF:

0.000672

GnomAD4 exome

AF:

0.000164

AC:

180

AN:

1097035

Hom.:

Cov.:

AF XY:

0.000157

AC XY:

AN XY:

362417

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26375

American (AMR)

AF:

0.00

AC:

AN:

35030

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19362

East Asian (EAS)

AF:

0.00

AC:

AN:

30196

South Asian (SAS)

AF:

0.00

AC:

AN:

53791

European-Finnish (FIN)

AF:

0.00304

AC:

123

AN:

40492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.0000558

AC:

AN:

841599

Other (OTH)

AF:

0.000217

AC:

AN:

46057

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000143

AC:

AN:

111560

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

33744

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30689

American (AMR)

AF:

0.00

AC:

AN:

10525

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3552

South Asian (SAS)

AF:

0.00

AC:

AN:

2672

European-Finnish (FIN)

AF:

0.00216

AC:

AN:

6013

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0000566

AC:

AN:

53038

Other (OTH)

AF:

0.00

AC:

AN:

1519

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.0000427

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000239

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.35

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.0096

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

-0.94

PhyloP100

1.7

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.37

REVEL

Uncertain

0.34

Sift

Benign

0.95

Sift4G

Benign

0.61

Polyphen

0.0

Vest4

0.079

MVP

0.82

MPC

1.1

ClinPred

0.023

GERP RS

4.3

Varity_R

0.20

gMVP

0.94

Mutation Taster

=98/2

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over