12-64194292-G-T

Variant names:

• chr12-64194292-G-T
• NM_152440.5:c.888C>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_152440.5(KICS2):​c.888C>A​(p.Asp296Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,840 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (1 hom.)
• Consequence: KICS2 NM_152440.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.35

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]

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, 0.889
• PP5: Variant 12-64194292-G-T is Pathogenic according to our data. Variant chr12-64194292-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 3747844.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KICS2	NM_152440.5	c.888C>A	p.Asp296Glu	missense_variant	Exon 3 of 3	ENST00000398055.8	NP_689653.4
KICS2	NM_001300940.2	c.888C>A	p.Asp296Glu	missense_variant	Exon 3 of 4		NP_001287869.2
KICS2	NM_001300941.2	c.729C>A	p.Asp243Glu	missense_variant	Exon 3 of 3		NP_001287870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KICS2	ENST00000398055.8	c.888C>A	p.Asp296Glu	missense_variant	Exon 3 of 3	1	NM_152440.5	ENSP00000381132.4
KICS2	ENST00000311915.12	c.888C>A	p.Asp296Glu	missense_variant	Exon 3 of 4	1		ENSP00000311486.8
KICS2	ENST00000544871.1	c.729C>A	p.Asp243Glu	missense_variant	Exon 3 of 3	2		ENSP00000445481.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461840 Hom.: 1 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual developmental disorder, autosomal recessive 83 Pathogenic:1

Feb 19, 2025

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;.;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;.;D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Benign	-0.65	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.91
MutPred		0.70		Gain of catalytic residue at P295 (P = 0.0017);Gain of catalytic residue at P295 (P = 0.0017);.;
MVP		0.65
MPC		1.1
ClinPred		0.99	D
GERP RS		4.3
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-64588072;