1-154726011-C-T

Variant names:

• chr1-154726011-C-T
• NM_002249.6:c.1606G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_002249.6(KCNN3):​c.1606G>A​(p.Ala536Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KCNN3 NM_002249.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P: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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778
• PP5: Variant 1-154726011-C-T is Pathogenic according to our data. Variant chr1-154726011-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1064423.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.1606G>A	p.Ala536Thr	missense_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.1606G>A	p.Ala536Thr	missense_variant	Exon 5 of 8	1	NM_002249.6	ENSP00000271915.3
KCNN3	ENST00000361147.8	c.691G>A	p.Ala231Thr	missense_variant	Exon 5 of 8	1		ENSP00000354764.4
KCNN3	ENST00000358505.2	c.667G>A	p.Ala223Thr	missense_variant	Exon 5 of 8	1		ENSP00000351295.2
KCNN3	ENST00000618040.4	c.1651G>A	p.Ala551Thr	missense_variant	Exon 6 of 9	5		ENSP00000481848.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Zimmermann-laband syndrome 3 Pathogenic:1

Nov 18, 2020

Molecular Genetics Laboratory, Motol Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

We identified a de novo variant Ala536Thr in monozygotic twins who were presented with clinical symptoms of Zimmerman-Laband syndrome. There was no evidence for mosaicism in healthy family members. The variant is not present in population databases (GnomAD, ExAC, 1000G). The locus is highly conserved in evolution: PhyloP 5,77; PhasCons 1. In silico predictors - SIFT, DANN, and Mutation Taster predicted a deleterious effect on protein structure. According to ACMG criteria, we classified the variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	.;D;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Benign	-0.85	T
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.5	D;.;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0070	D;.;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.39	.;.;B;.
Vest4		0.96
MVP		0.79
MPC		1.5
ClinPred		0.96	D
GERP RS		4.4
Varity_R		0.34
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr1-154698487;