Genetic Variant KCNN1:p.Arg53Pro (chr19-17974046-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001386974.1(KCNN1):c.158G>C(p.Arg53Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,457,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R53Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

KCNN1
NM_001386974.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0690

Publications

0 publications found

Variant links:

Genes affected

KCNN1 (HGNC:6290): (potassium calcium-activated channel subfamily N member 1) Action potentials in vertebrate neurons are followed by an afterhyperpolarization (AHP) that may persist for several seconds and may have profound consequences for the firing pattern of the neuron. Each component of the AHP is kinetically distinct and is mediated by different calcium-activated potassium channels. The protein encoded by this gene is activated before membrane hyperpolarization and is thought to regulate neuronal excitability by contributing to the slow component of synaptic AHP. The encoded protein is an integral membrane protein that forms a voltage-independent calcium-activated channel with three other calmodulin-binding subunits. This gene is a member of the KCNN family of potassium channel genes. [provided by RefSeq, Jul 2008]

KCNN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09048277).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN1	NM_001386974.1 link	c.158G>C	p.Arg53Pro	missense_variant	Exon 2 of 10	ENST00000684775.1	NP_001373903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN1	ENST00000684775.1 link	c.158G>C	p.Arg53Pro	missense_variant	Exon 2 of 10		NM_001386974.1	ENSP00000507021.1		Q92952-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000843

AC:

AN:

237298

AF XY:

0.0000153

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000571

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1457934

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725390

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44468

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26052

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39628

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51064

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111196

Other (OTH)

AF:

0.0000166

AC:

AN:

60246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000832

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.20

CADD

Benign

3.7

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.22

T;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.51

T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.090

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.;.

PhyloP100

-0.069

PrimateAI

Benign

0.44

REVEL

Benign

0.021

Sift4G

Benign

0.27

T;T;T

Polyphen

0.23

B;.;.

Vest4

0.088

MutPred

0.33

Gain of catalytic residue at R53 (P = 0.004);.;Gain of catalytic residue at R53 (P = 0.004);

MVP

0.24

MPC

0.73

ClinPred

0.15

GERP RS

-0.97

Varity_R

0.17

gMVP

0.36

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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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19-17974046-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over