rs1051614

Variant names:

• chr1-154772331-C-G
• rs1051614
• NM_002249.6:c.1092G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-154772331-C-G
• chr1-154772331-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002249.6(KCNN3):​c.1092G>C​(p.Leu364Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.589 in 1,613,672 control chromosomes in the GnomAD database, including 282,116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24504 hom., cov: 34)
  • Exomes 𝑓: 0.59 (257612 hom.)
• Consequence: KCNN3 NM_002249.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.146
• Publications: 26 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)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 1-154772331-C-G is Benign according to our data. Variant chr1-154772331-C-G is described in ClinVar as Benign. ClinVar VariationId is 403001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.146 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.1092G>C	p.Leu364Leu	synonymous_variant	Exon 3 of 8	ENST00000271915.9	NP_002240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN3	ENST00000271915.9	c.1092G>C	p.Leu364Leu	synonymous_variant	Exon 3 of 8	1	NM_002249.6	ENSP00000271915.3
KCNN3	ENST00000361147.8	c.177G>C	p.Leu59Leu	synonymous_variant	Exon 3 of 8	1		ENSP00000354764.4
KCNN3	ENST00000358505.2	c.153G>C	p.Leu51Leu	synonymous_variant	Exon 3 of 8	1		ENSP00000351295.2
KCNN3	ENST00000618040.4	c.1092G>C	p.Leu364Leu	synonymous_variant	Exon 3 of 9	5		ENSP00000481848.1

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85736 AN: 152054 Hom.: 24490 Cov.: 34

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.663

Gnomad EAS AF: 0.523

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.704

Gnomad NFE AF: 0.601

Gnomad OTH AF: 0.582

GnomAD2 exomes AF: 0.581 AC: 145284 AN: 250190 AF XY: 0.589

Gnomad AFR exome AF: 0.491

Gnomad AMR exome AF: 0.490

Gnomad ASJ exome AF: 0.668

Gnomad EAS exome AF: 0.515

Gnomad FIN exome AF: 0.606

Gnomad NFE exome AF: 0.598

Gnomad OTH exome AF: 0.585

GnomAD4 exome AF: 0.592 AC: 865456 AN: 1461500 Hom.: 257612 Cov.: 55 AF XY: 0.595 AC XY: 432451 AN XY: 727058

African (AFR) AF: 0.490 AC: 16407 AN: 33478

American (AMR) AF: 0.488 AC: 21806 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.660 AC: 17259 AN: 26132

East Asian (EAS) AF: 0.529 AC: 20998 AN: 39688

South Asian (SAS) AF: 0.656 AC: 56587 AN: 86246

European-Finnish (FIN) AF: 0.599 AC: 31967 AN: 53368

Middle Eastern (MID) AF: 0.667 AC: 3850 AN: 5768

European-Non Finnish (NFE) AF: 0.594 AC: 660815 AN: 1111762

Other (OTH) AF: 0.592 AC: 35767 AN: 60390

GnomAD4 genome AF: 0.564 AC: 85787 AN: 152172 Hom.: 24504 Cov.: 34 AF XY: 0.566 AC XY: 42083 AN XY: 74400

African (AFR) AF: 0.490 AC: 20327 AN: 41510

American (AMR) AF: 0.528 AC: 8073 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.663 AC: 2303 AN: 3472

East Asian (EAS) AF: 0.522 AC: 2696 AN: 5164

South Asian (SAS) AF: 0.644 AC: 3109 AN: 4830

European-Finnish (FIN) AF: 0.613 AC: 6492 AN: 10596

Middle Eastern (MID) AF: 0.705 AC: 206 AN: 292

European-Non Finnish (NFE) AF: 0.601 AC: 40865 AN: 67986

Other (OTH) AF: 0.583 AC: 1233 AN: 2114

Alfa AF: 0.536 Hom.: 2949

Bravo AF: 0.557

EpiCase AF: 0.614

EpiControl AF: 0.619

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Zimmermann-Laband syndrome 3 Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.3
DANN	Benign	0.74
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

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: rs1051614; hg19: chr1-154744807; COSMIC: COSV55222851;