NM_002249.6:c.1571G>C

Variant names:

• chr1-154733022-C-G
• NM_002249.6:c.1571G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002249.6(KCNN3):​c.1571G>C​(p.Cys524Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNN3 NM_002249.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.1571G>C	p.Cys524Ser	missense_variant	Exon 4 of 8	ENST00000271915.9	NP_002240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN3	ENST00000271915.9	c.1571G>C	p.Cys524Ser	missense_variant	Exon 4 of 8	1	NM_002249.6	ENSP00000271915.3
KCNN3	ENST00000361147.8	c.656G>C	p.Cys219Ser	missense_variant	Exon 4 of 8	1		ENSP00000354764.4
KCNN3	ENST00000358505.2	c.632G>C	p.Cys211Ser	missense_variant	Exon 4 of 8	1		ENSP00000351295.2
KCNN3	ENST00000618040.4	c.1616G>C	p.Cys539Ser	missense_variant	Exon 5 of 9	5		ENSP00000481848.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 09, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;T;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Benign	-1.0	T
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.5	D;.;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.14	T;.;T;T
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.21	.;.;B;.
Vest4		0.85
MVP		0.57
MPC		2.2
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.49
gMVP		0.99

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-154705498;