Genetic Variant KCNIP4:p.Asn137Ile (chr4-20749681-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_025221.6(KCNIP4):c.410A>T(p.Asn137Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. N137S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

KCNIP4
NM_025221.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.68

Publications

0 publications found

Variant links:

Genes affected

KCNIP4 (HGNC:30083): (potassium voltage-gated channel interacting protein 4) This gene encodes a member of the family of voltage-gated potassium (Kv) channel-interacting proteins (KCNIPs), which belong to the recoverin branch of the EF-hand superfamily. Members of the KCNIP family are small calcium binding proteins. They all have EF-hand-like domains, and differ from each other in the N-terminus. They are integral subunit components of native Kv4 channel complexes. They may regulate A-type currents, and hence neuronal excitability, in response to changes in intracellular calcium. This protein member also interacts with presenilin. Multiple alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

KCNIP4 links:

PACRGL (HGNC:28442): (parkin coregulated like)

PACRGL links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.775

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025221.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNIP4	NM_025221.6	MANE Select	c.410A>T	p.Asn137Ile	missense	Exon 5 of 9	NP_079497.2
KCNIP4	NM_001363504.2		c.359A>T	p.Asn120Ile	missense	Exon 4 of 8	NP_001350433.1	Q3YAB7
KCNIP4	NM_147183.3		c.347A>T	p.Asn116Ile	missense	Exon 4 of 8	NP_671712.1	Q6PIL6-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNIP4	ENST00000382152.7	TSL:5 MANE Select	c.410A>T	p.Asn137Ile	missense	Exon 5 of 9	ENSP00000371587.2	Q6PIL6-1
KCNIP4	ENST00000382149.9	TSL:1	c.359A>T	p.Asn120Ile	missense	Exon 4 of 8	ENSP00000494651.1	Q3YAB7
KCNIP4	ENST00000382150.8	TSL:1	c.347A>T	p.Asn116Ile	missense	Exon 4 of 8	ENSP00000371585.4	Q6PIL6-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249864

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.78

MetaSVM

Uncertain

0.48

MutationAssessor

Pathogenic

2.9

PhyloP100

2.7

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.2

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0080

Polyphen

0.76

Vest4

0.62

MutPred

0.58

Loss of disorder (P = 0.0644)

MVP

0.75

MPC

1.6

ClinPred

0.99

GERP RS

5.6

Varity_R

0.77

gMVP

0.89

Mutation Taster

=61/39

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over