rs2239751

Variant names:

• chr3-50610457-T-G
• rs2239751
• ENST00000491847.1:n.1305A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000491847.1(CISH):​n.1305A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,551,374 control chromosomes in the GnomAD database, including 5,906 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.073 (1095 hom., cov: 33)
  • Exomes 𝑓: 0.031 (4811 hom.)
• Consequence: CISH ENST00000491847.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0450
• Publications: 22 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000491847.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CISH	NM_145071.4	MANE Select	c.20+1174A>C		intron	N/A	NP_659508.1
	CISH	NM_013324.7		c.-14A>C		5_prime_UTR	Exon 2 of 4	NP_037456.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CISH	ENST00000491847.1	TSL:1	n.1305A>C		non_coding_transcript_exon	Exon 1 of 2
	CISH	ENST00000443053.6	TSL:1	c.-14A>C		5_prime_UTR	Exon 2 of 4	ENSP00000409346.2
	CISH	ENST00000348721.4	TSL:1 MANE Select	c.20+1174A>C		intron	N/A	ENSP00000294173.3

Frequencies

GnomAD3 genomes AF: 0.0734 AC: 11157 AN: 152060 Hom.: 1089 Cov.: 33

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00967

Gnomad OTH AF: 0.0627

GnomAD2 exomes AF: 0.0963 AC: 15050 AN: 156318 AF XY: 0.0803

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.362

Gnomad ASJ exome AF: 0.0196

Gnomad EAS exome AF: 0.336

Gnomad FIN exome AF: 0.00238

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.0688

GnomAD4 exome AF: 0.0311 AC: 43521 AN: 1399196 Hom.: 4811 Cov.: 29 AF XY: 0.0292 AC XY: 20117 AN XY: 690116

African (AFR) AF: 0.131 AC: 4152 AN: 31590

American (AMR) AF: 0.335 AC: 11977 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 477 AN: 25180

East Asian (EAS) AF: 0.324 AC: 11594 AN: 35736

South Asian (SAS) AF: 0.0176 AC: 1394 AN: 79228

European-Finnish (FIN) AF: 0.00272 AC: 134 AN: 49272

Middle Eastern (MID) AF: 0.0342 AC: 191 AN: 5584

European-Non Finnish (NFE) AF: 0.0100 AC: 10834 AN: 1078928

Other (OTH) AF: 0.0477 AC: 2768 AN: 57976

GnomAD4 genome AF: 0.0735 AC: 11184 AN: 152178 Hom.: 1095 Cov.: 33 AF XY: 0.0766 AC XY: 5699 AN XY: 74416

African (AFR) AF: 0.123 AC: 5115 AN: 41484

American (AMR) AF: 0.220 AC: 3357 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3472

East Asian (EAS) AF: 0.330 AC: 1702 AN: 5164

South Asian (SAS) AF: 0.0292 AC: 141 AN: 4826

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10610

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00967 AC: 658 AN: 68012

Other (OTH) AF: 0.0616 AC: 130 AN: 2112

Alfa AF: 0.0402 Hom.: 196

Bravo AF: 0.0946

Asia WGS AF: 0.141 AC: 489 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	12
DANN	Benign	0.69
PhyloP100		-0.045
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2239751; hg19: chr3-50647888; COSMIC: COSV62295434; COSMIC: COSV62295434;