2-95382389-A-G

Variant names:

• chr2-95382389-A-G
• NM_013434.5:c.568A>G

Variant summary

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

The NM_013434.5(KCNIP3):​c.568A>G​(p.Ile190Val) 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: 33)
• Consequence: KCNIP3 NM_013434.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.44

Genes affected

KCNIP3 (HGNC:15523): (potassium voltage-gated channel interacting protein 3) This gene encodes a member of the family of voltage-gated potassium (Kv) channel-interacting proteins, which belong to the recoverin branch of the EF-hand superfamily. Members of this family are small calcium binding proteins containing EF-hand-like domains. They are integral subunit components of native Kv4 channel complexes that may regulate A-type currents, and hence neuronal excitability, in response to changes in intracellular calcium. The encoded protein also functions as a calcium-regulated transcriptional repressor, and interacts with presenilins. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

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
KCNIP3	NM_013434.5	c.568A>G	p.Ile190Val	missense_variant	Exon 7 of 9	ENST00000295225.10	NP_038462.1
KCNIP3	NM_001034914.2	c.490A>G	p.Ile164Val	missense_variant	Exon 6 of 8		NP_001030086.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNIP3	ENST00000295225.10	c.568A>G	p.Ile190Val	missense_variant	Exon 7 of 9	1	NM_013434.5	ENSP00000295225.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.568A>G (p.I190V) alteration is located in exon 7 (coding exon 7) of the KCNIP3 gene. This alteration results from a A to G substitution at nucleotide position 568, causing the isoleucine (I) at amino acid position 190 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	0.0088	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	-0.35	N;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.84	N;.;N
REVEL	Uncertain	0.45
Sift	Benign	0.26	T;.;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.73	P;.;B
Vest4		0.62
MutPred		0.68		Gain of catalytic residue at I190 (P = 0.008);Gain of catalytic residue at I190 (P = 0.008);.;
MVP		0.55
MPC		1.1
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.28
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr2-96048137;