chr1-154725917-C-A

Variant names:

• chr1-154725917-C-A
• NM_002249.6:c.1700G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002249.6(KCNN3):​c.1700G>T​(p.Arg567Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,460,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R567Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNN3 NM_002249.6 missense, splice_region
• Scores: Splicing: ADA: 0.9927
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.1700G>T	p.Arg567Leu	missense_variant, splice_region_variant	Exon 5 of 8	ENST00000271915.9	NP_002240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN3	ENST00000271915.9	c.1700G>T	p.Arg567Leu	missense_variant, splice_region_variant	Exon 5 of 8	1	NM_002249.6	ENSP00000271915.3
KCNN3	ENST00000361147.8	c.785G>T	p.Arg262Leu	missense_variant, splice_region_variant	Exon 5 of 8	1		ENSP00000354764.4
KCNN3	ENST00000358505.2	c.761G>T	p.Arg254Leu	missense_variant, splice_region_variant	Exon 5 of 8	1		ENSP00000351295.2
KCNN3	ENST00000618040.4	c.1745G>T	p.Arg582Leu	missense_variant, splice_region_variant	Exon 6 of 9	5		ENSP00000481848.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460416 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726600

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Benign	-0.83	T
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.1	D;.;D;D
REVEL	Uncertain	0.47
Sift	Benign	0.083	T;.;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.72	.;.;P;.
Vest4		0.81
MVP		0.67
MPC		1.5
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.36
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.86
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-154698393; COSMIC: COSV99677739;