Genetic Variant NM_152440.5:c.352G>T (chr12-64215847-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152440.5(KICS2):c.352G>T(p.Val118Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 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. V118M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KICS2
NM_152440.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.88

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

KICS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05139938).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152440.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KICS2	NM_152440.5	MANE Select	c.352G>T	p.Val118Leu	missense	Exon 2 of 3	NP_689653.4
KICS2	NM_001300940.2		c.352G>T	p.Val118Leu	missense	Exon 2 of 4	NP_001287869.2	J3KNH0
KICS2	NM_001300941.2		c.193G>T	p.Val65Leu	missense	Exon 2 of 3	NP_001287870.2	F5H2Q3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KICS2	ENST00000398055.8	TSL:1 MANE Select	c.352G>T	p.Val118Leu	missense	Exon 2 of 3	ENSP00000381132.4	Q96MD2
KICS2	ENST00000311915.12	TSL:1	c.352G>T	p.Val118Leu	missense	Exon 2 of 4	ENSP00000311486.8	J3KNH0
KICS2	ENST00000907624.1		c.352G>T	p.Val118Leu	missense	Exon 2 of 4	ENSP00000577683.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461564

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727048

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111898

Other (OTH)

AF:

0.00

AC:

AN:

60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

4.7

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.0014

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.83

M_CAP

Benign

0.0070

MetaRNN

Benign

0.051

MetaSVM

Benign

-1.0

PhyloP100

1.9

PROVEAN

Benign

0.35

REVEL

Benign

0.068

Sift

Benign

0.66

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.064

MutPred

0.34

Gain of catalytic residue at T114 (P = 0.0026)

MVP

0.082

MPC

0.35

ClinPred

0.074

GERP RS

0.41

gMVP

0.19

Mutation Taster

=94/6

polymorphism

(source)

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

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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