Genetic Variant KCNN1:p.Gly22Arg (chr19-17973952-G-A) – 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.64G>A(p.Gly22Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000994 in 1,408,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000099 ( 0 hom. )

Consequence

KCNN1
NM_001386974.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.638

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=0.0971286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN1	NM_001386974.1 link	c.64G>A	p.Gly22Arg	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.64G>A	p.Gly22Arg	missense_variant	Exon 2 of 10		NM_001386974.1	ENSP00000507021.1		Q92952-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000127

AC:

AN:

157468

AF XY:

0.0000232

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:

0.00

Gnomad NFE exome

AF:

0.0000322

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000994

AC:

AN:

1408332

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

696342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32146

American (AMR)

AF:

0.00

AC:

AN:

36438

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

36638

South Asian (SAS)

AF:

0.00

AC:

AN:

80884

European-Finnish (FIN)

AF:

0.0000433

AC:

AN:

46194

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.0000110

AC:

AN:

1086680

Other (OTH)

AF:

0.00

AC:

AN:

58472

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000883

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 11, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.64G>A (p.G22R) alteration is located in exon 3 (coding exon 1) of the KCNN1 gene. This alteration results from a G to A substitution at nucleotide position 64, causing the glycine (G) at amino acid position 22 to be replaced by an arginine (R). 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

0.11

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.27

CADD

Benign

6.1

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.17

T;.;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.75

T;T;T

M_CAP

Benign

0.0066

MetaRNN

Benign

0.097

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;.;.

PhyloP100

0.64

PrimateAI

Uncertain

0.56

REVEL

Benign

0.050

Sift4G

Benign

1.0

T;T;T

Polyphen

0.62

P;.;.

Vest4

0.14

MutPred

0.28

Gain of methylation at G22 (P = 0.0383);.;Gain of methylation at G22 (P = 0.0383);

MVP

0.22

MPC

0.61

ClinPred

0.12

GERP RS

2.2

Varity_R

0.035

gMVP

0.27

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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19-17973952-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over