rs2239751

chr3-50610457-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000443053.6(CISH):c.-14A>C variant causes a 5 prime UTR 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 ENST00000443053.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0450

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CISH	NM_145071.4	c.20+1174A>C		intron_variant		ENST00000348721.4
CISH	NM_013324.7	c.-14A>C		5_prime_UTR_variant	2/4
CISH	XM_047447398.1	c.-14A>C		5_prime_UTR_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CISH	ENST00000443053.6	c.-14A>C		5_prime_UTR_variant	2/4	1
CISH	ENST00000348721.4	c.20+1174A>C		intron_variant		1	NM_145071.4	P1
CISH	ENST00000491847.1	n.1305A>C		non_coding_transcript_exon_variant	1/2	1

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

GnomAD3 exomes AF: 0.0963 AC: 15050 AN: 156318 Hom.: 2534 AF XY: 0.0803 AC XY: 6650 AN XY: 82806

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 SAS exome AF: 0.0165

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

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.335

Gnomad4 ASJ exome AF: 0.0189

Gnomad4 EAS exome AF: 0.324

Gnomad4 SAS exome AF: 0.0176

Gnomad4 FIN exome AF: 0.00272

Gnomad4 NFE exome AF: 0.0100

Gnomad4 OTH exome AF: 0.0477

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

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.220

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.330

Gnomad4 SAS AF: 0.0292

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00967

Gnomad4 OTH AF: 0.0616

Alfa AF: 0.0383 Hom.: 101

Bravo AF: 0.0946

Asia WGS AF: 0.141 AC: 489 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	12
Dann	Benign	0.69

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