5-114362567-A-C

Position:

• chr5-114362567-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. 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. 7/8 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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 242 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNN2	NM_021614.4	c.428A>C	p.Tyr143Ser	missense_variant	1/8	ENST00000673685.1	NP_067627.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNN2	ENST00000673685.1	c.428A>C	p.Tyr143Ser	missense_variant	1/8		NM_021614.4	ENSP00000501239.1
KCNN2	ENST00000512097.10	c.626A>C	p.Tyr209Ser	missense_variant	6/13	5		ENSP00000427120.4

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

Gnomad4 AFR exome AF: 0.000512

Gnomad4 AMR exome AF: 0.00374

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000601

Gnomad4 SAS exome AF: 0.0306

Gnomad4 FIN exome AF: 0.000205

Gnomad4 NFE exome AF: 0.000163

Gnomad4 OTH exome AF: 0.00138

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

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000972

Gnomad4 SAS AF: 0.0348

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.0000695 Hom.: 0

Bravo AF: 0.000971

Asia WGS AF: 0.0140 AC: 47 AN: 3472

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonia 34, myoclonic Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant c.428A>C p.Tyr143Ser in KCNN2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.03% in the gnomAD Exomes and novel in 1000 Genomes. The amino acid Tyrosine at position 143 is changed to a Serine changing protein sequence and it might alter its composition and physico-chemical properties. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Neurodevelopmental disorder with or without variable movement or behavioral abnormalities Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Jun 22, 2023

The observed missense c.428A>Cp.Tyr143Ser variant in KCNN2 gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Tyr143Ser variant is present with allele frequency of 0.03% in gnomAD Exomes. This variant has not been submitted to the ClinVar database. Multiple lines of computational evidences SIFT - Tolerated and MutationTaster - Disease causing predict conflicting evidence on protein structure and function for this variant. The amino acid Tyr at position 143 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance VUS. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
GERP RS		-2.4

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

LitVar

Other links and lift over

dbSNP: rs373945997; hg19: chr5-113698264;