5-114463289-C-T

Variant names:

• chr5-114463289-C-T
• rs17136627
• NM_021614.4:c.1779+99C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021614.4(KCNN2):​c.1779+99C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.044 in 895,398 control chromosomes in the GnomAD database, including 1,433 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.073 (681 hom., cov: 33)
  • Exomes 𝑓: 0.038 (752 hom.)
• Consequence: KCNN2 NM_021614.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.219
• Publications: 14 publications found

Genes affected

KCNN2 (HGNC:6291): (potassium calcium-activated channel subfamily N member 2) 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. This gene is a member of the KCNN family of potassium channel genes. The encoded protein is an integral membrane protein that forms a voltage-independent calcium-activated channel with three other calmodulin-binding subunits. Alternate splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

KCNN2 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with or without variable movement or behavioral abnormalities

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)

LOC101927078 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021614.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN2	NM_021614.4	MANE Select	c.1779+99C>T		intron	N/A	NP_067627.3
	KCNN2	NM_001372233.1		c.1977+99C>T		intron	N/A	NP_001359162.1
	KCNN2	NM_170775.3		c.99+99C>T		intron	N/A	NP_740721.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN2	ENST00000673685.1	MANE Select	c.1779+99C>T		intron	N/A	ENSP00000501239.1
	KCNN2	ENST00000503706.5	TSL:1	c.99+99C>T		intron	N/A	ENSP00000421439.1
	KCNN2	ENST00000512097.10	TSL:5	c.1977+99C>T		intron	N/A	ENSP00000427120.4

Frequencies

GnomAD3 genomes AF: 0.0726 AC: 11045 AN: 152126 Hom.: 678 Cov.: 33

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0367

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.0397

Gnomad SAS AF: 0.0745

Gnomad FIN AF: 0.0555

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0334

Gnomad OTH AF: 0.0627

GnomAD4 exome AF: 0.0381 AC: 28345 AN: 743154 Hom.: 752 AF XY: 0.0386 AC XY: 14696 AN XY: 380870

African (AFR) AF: 0.159 AC: 2749 AN: 17342

American (AMR) AF: 0.0228 AC: 531 AN: 23328

Ashkenazi Jewish (ASJ) AF: 0.0226 AC: 346 AN: 15324

East Asian (EAS) AF: 0.0251 AC: 833 AN: 33220

South Asian (SAS) AF: 0.0674 AC: 3131 AN: 46476

European-Finnish (FIN) AF: 0.0543 AC: 2475 AN: 45606

Middle Eastern (MID) AF: 0.0379 AC: 123 AN: 3248

European-Non Finnish (NFE) AF: 0.0317 AC: 16597 AN: 523906

Other (OTH) AF: 0.0450 AC: 1560 AN: 34704

GnomAD4 genome AF: 0.0727 AC: 11066 AN: 152244 Hom.: 681 Cov.: 33 AF XY: 0.0742 AC XY: 5525 AN XY: 74430

African (AFR) AF: 0.165 AC: 6859 AN: 41516

American (AMR) AF: 0.0366 AC: 560 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3472

East Asian (EAS) AF: 0.0399 AC: 207 AN: 5182

South Asian (SAS) AF: 0.0739 AC: 357 AN: 4828

European-Finnish (FIN) AF: 0.0555 AC: 589 AN: 10606

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0334 AC: 2269 AN: 68026

Other (OTH) AF: 0.0626 AC: 132 AN: 2110

Alfa AF: 0.0505 Hom.: 581

Bravo AF: 0.0734

Asia WGS AF: 0.0630 AC: 219 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.0
DANN	Benign	0.75
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17136627; hg19: chr5-113798986;