1-154869723-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT-GGCTGCTGCTGCTGCT

Variant names:

• chr1-154869723-GGCTGCTGCTGCTGCT-G
• rs3831942
• NM_002249.6:c.227_241delAGCAGCAGCAGCAGC

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP3 BP6_Moderate

The NM_002249.6(KCNN3):​c.227_241delAGCAGCAGCAGCAGC​(p.Gln76_Gln80del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,506,508 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: KCNN3 NM_002249.6 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.39
• 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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: Likely_benign. The variant received -3 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_002249.6
• BP6: Variant 1-154869723-GGCTGCTGCTGCTGCT-G is Benign according to our data. Variant chr1-154869723-GGCTGCTGCTGCTGCT-G is described in ClinVar as Benign. ClinVar VariationId is 1685505.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN3	NM_002249.6	MANE Select	c.227_241delAGCAGCAGCAGCAGC	p.Gln76_Gln80del	disruptive_inframe_deletion	Exon 1 of 8	NP_002240.3
	KCNN3	NM_001204087.2		c.227_241delAGCAGCAGCAGCAGC	p.Gln76_Gln80del	disruptive_inframe_deletion	Exon 1 of 9	NP_001191016.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN3	ENST00000271915.9	TSL:1 MANE Select	c.227_241delAGCAGCAGCAGCAGC	p.Gln76_Gln80del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000271915.3
	KCNN3	ENST00000618040.4	TSL:5	c.227_241delAGCAGCAGCAGCAGC	p.Gln76_Gln80del	disruptive_inframe_deletion	Exon 1 of 9	ENSP00000481848.1
	ENSG00000308854	ENST00000836873.1		n.195-631_195-617delCTGCTGCTGCTGCTG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000503 AC: 71 AN: 141288 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000954

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000212

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000648

Gnomad SAS AF: 0.000988

Gnomad FIN AF: 0.000110

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000273 AC: 373 AN: 1365118 Hom.: 1 AF XY: 0.000277 AC XY: 187 AN XY: 674884

African (AFR) AF: 0.000289 AC: 9 AN: 31108

American (AMR) AF: 0.0000563 AC: 2 AN: 35508

Ashkenazi Jewish (ASJ) AF: 0.000120 AC: 3 AN: 24960

East Asian (EAS) AF: 0.000365 AC: 13 AN: 35568

South Asian (SAS) AF: 0.000406 AC: 32 AN: 78750

European-Finnish (FIN) AF: 0.0000217 AC: 1 AN: 46140

Middle Eastern (MID) AF: 0.000226 AC: 1 AN: 4434

European-Non Finnish (NFE) AF: 0.000277 AC: 291 AN: 1051846

Other (OTH) AF: 0.000370 AC: 21 AN: 56804

GnomAD4 genome AF: 0.000502 AC: 71 AN: 141390 Hom.: 0 Cov.: 0 AF XY: 0.000588 AC XY: 40 AN XY: 68016

African (AFR) AF: 0.000951 AC: 36 AN: 37840

American (AMR) AF: 0.000212 AC: 3 AN: 14158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3376

East Asian (EAS) AF: 0.000650 AC: 3 AN: 4614

South Asian (SAS) AF: 0.000990 AC: 4 AN: 4042

European-Finnish (FIN) AF: 0.000110 AC: 1 AN: 9120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.000368 AC: 24 AN: 65186

Other (OTH) AF: 0.00 AC: 0 AN: 1902

Alfa AF: 0.00 Hom.: 292

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4
Mutation Taster		=171/29	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs3831942; hg19: chr1-154842199;