5-114362558-G-GGCAGCAGTACGC

Variant names:

• chr5-114362558-G-GGCAGCAGTACGC
• rs1242600338
• NM_021614.4:c.428_439dupACGCGCAGCAGT

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_021614.4(KCNN2):​c.428_439dupACGCGCAGCAGT​(p.Tyr143_Gln146dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 613,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: KCNN2 NM_021614.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_021614.4.
• BS2: High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN2	NM_021614.4	c.428_439dupACGCGCAGCAGT	p.Tyr143_Gln146dup	disruptive_inframe_insertion	Exon 1 of 8	ENST00000673685.1	NP_067627.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN2	ENST00000673685.1	c.428_439dupACGCGCAGCAGT	p.Tyr143_Gln146dup	disruptive_inframe_insertion	Exon 1 of 8		NM_021614.4	ENSP00000501239.1
KCNN2	ENST00000512097.10	c.626_637dupACGCGCAGCAGT	p.Tyr209_Gln212dup	disruptive_inframe_insertion	Exon 6 of 13	5		ENSP00000427120.4

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000933 AC: 43 AN: 460938 Hom.: 0 Cov.: 6 AF XY: 0.0000876 AC XY: 21 AN XY: 239774

Gnomad4 AFR exome AF: 0.000548

Gnomad4 AMR exome AF: 0.0000848

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000154

Gnomad4 SAS exome AF: 0.0000266

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000976

Gnomad4 OTH exome AF: 0.0000778

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74448

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonia 34, myoclonic Uncertain:1

Jun 19, 2023

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.428_439dup variant is not present in publicly available population databases like 1000 Genomes, ExAC, EVS, gnomAD, Indian Exome Database or our in-house exome database. This variant has neither been published in literature nor reported to clinical databases like in ClinVar, Human Gene Mutation Database (HGMD) or OMIM, in any affected individuals. In-silico pathogenicity prediction programs like MutationTaster2, CADD etc predicted this variant to be likely deleterious. This variant is located in a non-repetitive region of the gene that may alter the protein length by in-frame duplication of 4 amino acids. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1242600338; hg19: chr5-113698255;