Variant 3-50607852-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_145071.4(CISH):c.532C>T(p.Pro178Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CISH
NM_145071.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.83

Variant links:

Genes affected

CISH (HGNC:1984): (cytokine inducible SH2 containing protein) The protein encoded by this gene contains a SH2 domain and a SOCS box domain. The protein thus belongs to the cytokine-induced STAT inhibitor (CIS), also known as suppressor of cytokine signaling (SOCS) or STAT-induced STAT inhibitor (SSI), protein family. CIS family members are known to be cytokine-inducible negative regulators of cytokine signaling. The expression of this gene can be induced by IL2, IL3, GM-CSF and EPO in hematopoietic cells. Proteasome-mediated degradation of this protein has been shown to be involved in the inactivation of the erythropoietin receptor. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

CISH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.058359593).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CISH	NM_145071.4 linkuse as main transcript	c.532C>T	p.Pro178Ser	missense_variant	3/3	ENST00000348721.4
CISH	NM_013324.7 linkuse as main transcript	c.583C>T	p.Pro195Ser	missense_variant	4/4
CISH	XM_047447398.1 linkuse as main transcript	c.583C>T	p.Pro195Ser	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CISH	ENST00000348721.4 linkuse as main transcript	c.532C>T	p.Pro178Ser	missense_variant	3/3	1	NM_145071.4	P1	Q9NSE2-1
CISH	ENST00000443053.6 linkuse as main transcript	c.583C>T	p.Pro195Ser	missense_variant	4/4	1			Q9NSE2-3
CISH	ENST00000491847.1 linkuse as main transcript	n.3680C>T		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152188

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:

0.000384

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000519

AC:

AN:

250674

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135658

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000653

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461546

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000384

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2023

The c.583C>T (p.P195S) alteration is located in exon 4 (coding exon 3) of the CISH gene. This alteration results from a C to T substitution at nucleotide position 583, causing the proline (P) at amino acid position 195 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.058

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.18

N;N

REVEL

Benign

0.046

Sift

Benign

0.11

T;D

Sift4G

Benign

0.40

T;T

Polyphen

0.0030

.;B

Vest4

0.14

MutPred

0.25

.;Gain of phosphorylation at P178 (P = 0.0143);

MVP

0.54

MPC

0.31

ClinPred

0.079

GERP RS

5.0

Varity_R

0.067

gMVP

0.32

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over