NM_001386974.1:c.653C>T

Variant names:

• chr19-17981863-C-T
• rs1380127928
• NM_001386974.1:c.653C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001386974.1(KCNN1):​c.653C>T​(p.Ala218Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,260 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: 0.0000062 (0 hom.)
• Consequence: KCNN1 NM_001386974.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06272116).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386974.1. 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
	KCNN1	NM_001386974.1	MANE Select	c.653C>T	p.Ala218Val	missense	Exon 4 of 10	NP_001373903.1	Q92952-1
	KCNN1	NM_001386975.1		c.653C>T	p.Ala218Val	missense	Exon 4 of 11	NP_001373904.1	A0A804HIW7
	KCNN1	NM_001386976.1		c.653C>T	p.Ala218Val	missense	Exon 5 of 12	NP_001373905.1	A0A804HIW7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN1	ENST00000684775.1	MANE Select	c.653C>T	p.Ala218Val	missense	Exon 4 of 10	ENSP00000507021.1	Q92952-1
	KCNN1	ENST00000222249.13	TSL:1	c.653C>T	p.Ala218Val	missense	Exon 5 of 11	ENSP00000476519.1	Q92952-1
	KCNN1	ENST00000682733.1		c.653C>T	p.Ala218Val	missense	Exon 5 of 12	ENSP00000507255.1	A0A804HIW7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000407 AC: 1 AN: 245986 AF XY: 0.00000747

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: 0.00000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460260 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726334

African (AFR) AF: 0.0000299 AC: 1 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53060

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111214

Other (OTH) AF: 0.0000332 AC: 2 AN: 60294

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.29	N
PhyloP100		3.1
PrimateAI	Benign	0.39	T
REVEL	Benign	0.091
Sift4G	Benign	0.53	T
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.34		Gain of helix (P = 0.0325)
MVP		0.043
MPC		1.6
ClinPred		0.90	D
GERP RS		3.7
Varity_R		0.033
gMVP		0.69
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1380127928; hg19: chr19-18092672;