12-64193904-C-G

Variant names:

• chr12-64193904-C-G
• rs188114016
• NM_152440.5:c.1276G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152440.5(KICS2):​c.1276G>C​(p.Val426Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,614,120 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (21 hom.)
• Consequence: KICS2 NM_152440.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.18

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035472214).
• BP6: Variant 12-64193904-C-G is Benign according to our data. Variant chr12-64193904-C-G is described in ClinVar as [Benign]. Clinvar id is 790663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00792 (1206/152238) while in subpopulation AFR AF= 0.0263 (1093/41514). AF 95% confidence interval is 0.025. There are 17 homozygotes in gnomad4. There are 588 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KICS2	NM_152440.5	c.1276G>C	p.Val426Leu	missense_variant	Exon 3 of 3	ENST00000398055.8	NP_689653.4
KICS2	NM_001300940.2	c.1276G>C	p.Val426Leu	missense_variant	Exon 3 of 4		NP_001287869.2
KICS2	NM_001300941.2	c.1117G>C	p.Val373Leu	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.1276G>C	p.Val426Leu	missense_variant	Exon 3 of 3	1	NM_152440.5	ENSP00000381132.4
KICS2	ENST00000311915.12	c.1276G>C	p.Val426Leu	missense_variant	Exon 3 of 4	1		ENSP00000311486.8
KICS2	ENST00000544871.1	c.1117G>C	p.Val373Leu	missense_variant	Exon 3 of 3	2		ENSP00000445481.1

Frequencies

GnomAD3 genomes AF: 0.00786 AC: 1195 AN: 152120 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00256 AC: 639 AN: 249534 Hom.: 11 AF XY: 0.00206 AC XY: 279 AN XY: 135380

Gnomad AFR exome AF: 0.0293

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.00112 AC: 1630 AN: 1461882 Hom.: 21 Cov.: 34 AF XY: 0.00107 AC XY: 775 AN XY: 727242

Gnomad4 AFR exome AF: 0.0297

Gnomad4 AMR exome AF: 0.00221

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00199

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.00255

GnomAD4 genome AF: 0.00792 AC: 1206 AN: 152238 Hom.: 17 Cov.: 32 AF XY: 0.00790 AC XY: 588 AN XY: 74424

Gnomad4 AFR AF: 0.0263

Gnomad4 AMR AF: 0.00444

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.000737 Hom.: 1

Bravo AF: 0.00907

ESP6500AA AF: 0.0241 AC: 89

ESP6500EA AF: 0.000244 AC: 2

ExAC AF: 0.00302 AC: 365

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 14, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	13
DANN	Benign	0.36
DEOGEN2	Benign	0.0020	.;.;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.093	T;.;T
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Benign	-0.97	T
PROVEAN	Benign	0.43	N;N;N
REVEL	Benign	0.030
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.15
MVP		0.068
MPC		0.35
ClinPred		0.00047	T
GERP RS		3.1
gMVP		0.18

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

Other links and lift over

dbSNP: rs188114016; hg19: chr12-64587684;