chr5-114362567-A-C

Variant names:

• chr5-114362567-A-C
• rs373945997
• NM_021614.4:c.428A>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BS1_Supporting BS2

The NM_021614.4(KCNN2):​c.428A>C​(p.Tyr143Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 643,622 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (42 hom.)
• Consequence: KCNN2 NM_021614.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.304
• Publications: 0 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)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.2857 (below the threshold of 3.09). Trascript score misZ: 1.564 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder with or without variable movement or behavioral abnormalities.
• BP4: Computational evidence support a benign effect (MetaRNN=0.004327178).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00159 (242/152244) while in subpopulation SAS AF = 0.0348 (168/4828). AF 95% confidence interval is 0.0305. There are 3 homozygotes in GnomAd4. There are 167 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 242 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN2	NM_021614.4	MANE Select	c.428A>C	p.Tyr143Ser	missense	Exon 1 of 8	NP_067627.3
	KCNN2	NM_001372233.1		c.626A>C	p.Tyr209Ser	missense	Exon 6 of 13	NP_001359162.1	A0A3F2YNY5
	KCNN2	NR_174097.1		n.498A>C		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN2	ENST00000673685.1	MANE Select	c.428A>C	p.Tyr143Ser	missense	Exon 1 of 8	ENSP00000501239.1	A0A669KBH3
	KCNN2	ENST00000512097.10	TSL:5	c.626A>C	p.Tyr209Ser	missense	Exon 6 of 13	ENSP00000427120.4	A0A3F2YNY5
	KCNN2	ENST00000631899.2	TSL:5	c.-173A>C		upstream_gene	N/A	ENSP00000487849.2	A0A0J9YW81

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 242 AN: 152130 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000969

Gnomad SAS AF: 0.0348

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00287 AC: 1410 AN: 491378 Hom.: 42 Cov.: 6 AF XY: 0.00419 AC XY: 1069 AN XY: 255230

African (AFR) AF: 0.000512 AC: 5 AN: 9758

American (AMR) AF: 0.00374 AC: 48 AN: 12820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12826

East Asian (EAS) AF: 0.000601 AC: 16 AN: 26622

South Asian (SAS) AF: 0.0306 AC: 1243 AN: 40602

European-Finnish (FIN) AF: 0.000205 AC: 6 AN: 29292

Middle Eastern (MID) AF: 0.000491 AC: 1 AN: 2036

European-Non Finnish (NFE) AF: 0.000163 AC: 54 AN: 330602

Other (OTH) AF: 0.00138 AC: 37 AN: 26820

GnomAD4 genome AF: 0.00159 AC: 242 AN: 152244 Hom.: 3 Cov.: 33 AF XY: 0.00224 AC XY: 167 AN XY: 74424

African (AFR) AF: 0.000120 AC: 5 AN: 41560

American (AMR) AF: 0.00288 AC: 44 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000972 AC: 5 AN: 5146

South Asian (SAS) AF: 0.0348 AC: 168 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68010

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.0000695 Hom.: 0

Bravo AF: 0.000971

Asia WGS AF: 0.0140 AC: 47 AN: 3472

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dystonia 34, myoclonic (1)
-	1	-	Neurodevelopmental disorder with or without variable movement or behavioral abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.86
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0043	T
PhyloP100		-0.30
GERP RS		-2.4
PromoterAI		0.017	Neutral
Mutation Taster		=300/0	polymorphism

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: rs373945997; hg19: chr5-113698264;