dbSNP rs188114016: KICS2:p.Val426Phe (chr12-64193904-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152440.5(KICS2):c.1276G>T(p.Val426Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign 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. V426L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

KICS2
NM_152440.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.18

Variant links:

Genes affected

KICS2 (HGNC:26517): (KICSTOR subunit 2) Involved in cellular response to starvation; negative regulation of TORC1 signaling; and protein localization to lysosome. Located in intercellular bridge and lysosome. Part of KICSTOR complex. [provided by Alliance of Genome Resources, Apr 2022]

KICS2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09482932).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KICS2	NM_152440.5 link	c.1276G>T	p.Val426Phe	missense_variant	Exon 3 of 3	ENST00000398055.8	NP_689653.4	Q96MD2
KICS2	NM_001300940.2 link	c.1276G>T	p.Val426Phe	missense_variant	Exon 3 of 4		NP_001287869.2
KICS2	NM_001300941.2 link	c.1117G>T	p.Val373Phe	missense_variant	Exon 3 of 3		NP_001287870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KICS2	ENST00000398055.8 link	c.1276G>T	p.Val426Phe	missense_variant	Exon 3 of 3	1	NM_152440.5	ENSP00000381132.4	Q96MD2
KICS2	ENST00000311915.12 link	c.1276G>T	p.Val426Phe	missense_variant	Exon 3 of 4	1		ENSP00000311486.8	J3KNH0
KICS2	ENST00000544871.1 link	c.1117G>T	p.Val373Phe	missense_variant	Exon 3 of 3	2		ENSP00000445481.1	F5H2Q3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000281

AC:

AN:

249534

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135380

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000530

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000809

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000828

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.013

.;.;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.45

T;.;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.095

T;T;T

MetaSVM

Benign

-0.99

PROVEAN

Benign

-0.83

N;N;N

REVEL

Benign

0.051

Sift

Uncertain

0.018

D;D;D

Sift4G

Uncertain

0.052

T;T;D

Polyphen

0.0010

.;.;B

Vest4

0.34

MutPred

0.50

Gain of catalytic residue at N424 (P = 0.0197);Gain of catalytic residue at N424 (P = 0.0197);.;

MVP

0.10

MPC

0.47

ClinPred

0.077

GERP RS

3.1

gMVP

0.49

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over