3-50608381-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_145071.4(CISH):c.233G>A(p.Arg78Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000507 in 1,600,448 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00061 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (2 hom.)
• Consequence: CISH NM_145071.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.43

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008878231).
• BP6: Variant 3-50608381-C-T is Benign according to our data. Variant chr3-50608381-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 723118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CISH	NM_145071.4	c.233G>A	p.Arg78Gln	missense_variant	2/3	ENST00000348721.4
CISH	NM_013324.7	c.284G>A	p.Arg95Gln	missense_variant	3/4
CISH	XM_047447398.1	c.284G>A	p.Arg95Gln	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CISH	ENST00000348721.4	c.233G>A	p.Arg78Gln	missense_variant	2/3	1	NM_145071.4	P1
CISH	ENST00000443053.6	c.284G>A	p.Arg95Gln	missense_variant	3/4	1
CISH	ENST00000491847.1	n.3381G>A		non_coding_transcript_exon_variant	1/2	1

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152228 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000797 AC: 190 AN: 238340 Hom.: 2 AF XY: 0.000784 AC XY: 101 AN XY: 128836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000626

Gnomad ASJ exome AF: 0.00455

Gnomad EAS exome AF: 0.00646

Gnomad SAS exome AF: 0.000317

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000517

GnomAD4 exome AF: 0.000496 AC: 718 AN: 1448102 Hom.: 2 Cov.: 32 AF XY: 0.000482 AC XY: 347 AN XY: 719568

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000475

Gnomad4 ASJ exome AF: 0.00393

Gnomad4 EAS exome AF: 0.0110

Gnomad4 SAS exome AF: 0.000273

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000108

Gnomad4 OTH exome AF: 0.000653

GnomAD4 genome AF: 0.000610 AC: 93 AN: 152346 Hom.: 1 Cov.: 33 AF XY: 0.000711 AC XY: 53 AN XY: 74498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.0108

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000704 Hom.: 1

Bravo AF: 0.000608

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000725 AC: 88

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CISH-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 30, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	0.075
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T;T
MetaRNN	Benign	0.0089	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.29	N;N
REVEL	Benign	0.17
Sift	Benign	0.21	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.47	.;P
Vest4		0.41
MVP		0.51
MPC		0.44
ClinPred		0.052	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.33

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: rs148162012; hg19: chr3-50645812; COSMIC: COSV62294932; COSMIC: COSV62294932;