NM_002249.6:c.233_241dupAGCAGCAGC

Variant names:

• chr1-154869723-G-GGCTGCTGCT
• rs3831942
• NM_002249.6:c.233_241dupAGCAGCAGC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3 BP6 BA1

The NM_002249.6(KCNN3):​c.233_241dupAGCAGCAGC​(p.Gln78_Gln80dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.13 (1519 hom., cov: 0)
  • Exomes 𝑓: 0.12 (2021 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNN3 NM_002249.6 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.12
• Publications: 18 publications found

Genes affected

KCNN3 (HGNC:6292): (potassium calcium-activated channel subfamily N member 3) 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. This gene belongs to the KCNN family of potassium channels. It encodes an integral membrane protein that forms a voltage-independent calcium-activated channel, which is thought to regulate neuronal excitability by contributing to the slow component of synaptic AHP. This gene contains two CAG repeat regions in the coding sequence. It was thought that expansion of one or both of these repeats could lead to an increased susceptibility to schizophrenia or bipolar disorder, but studies indicate that this is probably not the case. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2011]

KCNN3 Gene-Disease associations (from GenCC):

• Zimmermann-Laband syndrome 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Zimmermann-Laband syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• schizophrenia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000308854 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_002249.6
• BP6: Variant 1-154869723-G-GGCTGCTGCT is Benign according to our data. Variant chr1-154869723-G-GGCTGCTGCT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 403006.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002249.6. 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
	KCNN3	NM_002249.6	MANE Select	c.233_241dupAGCAGCAGC	p.Gln78_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	NP_002240.3
	KCNN3	NM_001204087.2		c.233_241dupAGCAGCAGC	p.Gln78_Gln80dup	conservative_inframe_insertion	Exon 1 of 9	NP_001191016.1	A0A087WYJ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN3	ENST00000271915.9	TSL:1 MANE Select	c.233_241dupAGCAGCAGC	p.Gln78_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	ENSP00000271915.3	Q9UGI6-1
	KCNN3	ENST00000618040.4	TSL:5	c.233_241dupAGCAGCAGC	p.Gln78_Gln80dup	conservative_inframe_insertion	Exon 1 of 9	ENSP00000481848.1	A0A087WYJ0
	KCNN3	ENST00000874071.1		c.233_241dupAGCAGCAGC	p.Gln78_Gln80dup	conservative_inframe_insertion	Exon 1 of 7	ENSP00000544130.1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 18884 AN: 140982 Hom.: 1518 Cov.: 0

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.0819

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.126

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.119 AC: 156714 AN: 1321026 Hom.: 2021 Cov.: 112 AF XY: 0.119 AC XY: 77685 AN XY: 653388

African (AFR) AF: 0.207 AC: 6223 AN: 30048

American (AMR) AF: 0.0673 AC: 2342 AN: 34824

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2745 AN: 24480

East Asian (EAS) AF: 0.0183 AC: 634 AN: 34556

South Asian (SAS) AF: 0.137 AC: 10512 AN: 76820

European-Finnish (FIN) AF: 0.139 AC: 6080 AN: 43720

Middle Eastern (MID) AF: 0.136 AC: 598 AN: 4382

European-Non Finnish (NFE) AF: 0.119 AC: 121378 AN: 1017072

Other (OTH) AF: 0.113 AC: 6202 AN: 55124

GnomAD4 genome AF: 0.134 AC: 18902 AN: 141082 Hom.: 1519 Cov.: 0 AF XY: 0.135 AC XY: 9167 AN XY: 67870

African (AFR) AF: 0.209 AC: 7891 AN: 37720

American (AMR) AF: 0.0816 AC: 1154 AN: 14138

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 341 AN: 3372

East Asian (EAS) AF: 0.0113 AC: 52 AN: 4614

South Asian (SAS) AF: 0.133 AC: 536 AN: 4034

European-Finnish (FIN) AF: 0.137 AC: 1238 AN: 9054

Middle Eastern (MID) AF: 0.181 AC: 51 AN: 282

European-Non Finnish (NFE) AF: 0.113 AC: 7334 AN: 65098

Other (OTH) AF: 0.126 AC: 240 AN: 1900

Alfa AF: 0.126 Hom.: 292

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=75/25	polymorphism (auto)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3831942; hg19: chr1-154842199; COSMIC: COSV55214091; COSMIC: COSV55214091;