Variant 19-17985428-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001386974.1(KCNN1):c.1034G>T(p.Gly345Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,449,482 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KCNN1
NM_001386974.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.69

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:

KCNN1 (HGNC:):

KCNN1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.772

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNN1	NM_001386974.1 linkuse as main transcript	c.1034G>T	p.Gly345Val	missense_variant	5/10	ENST00000684775.1	NP_001373903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNN1	ENST00000684775.1 linkuse as main transcript	c.1034G>T	p.Gly345Val	missense_variant	5/10		NM_001386974.1	ENSP00000507021.1		Q92952-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000820

AC:

AN:

243788

Hom.:

AF XY:

0.00000756

AC XY:

AN XY:

132344

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000296

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1449482

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

720556

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000680

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2022

The c.1034G>T (p.G345V) alteration is located in exon 6 (coding exon 4) of the KCNN1 gene. This alteration results from a G to T substitution at nucleotide position 1034, causing the glycine (G) at amino acid position 345 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.021

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.78

N;.

PrimateAI

Pathogenic

0.91

REVEL

Uncertain

0.43

Sift4G

Benign

0.98

T;T

Polyphen

0.83

P;.

Vest4

0.86

MutPred

0.46

Gain of methylation at K344 (P = 0.0395);Gain of methylation at K344 (P = 0.0395);

MVP

0.83

MPC

2.6

ClinPred

0.93

GERP RS

4.9

Varity_R

0.77

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over