3-50607956-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_145071.4(CISH):c.428A>G(p.Asn143Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000303 in 1,613,956 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 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: CISH NM_145071.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.45

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 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=0.045812786).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CISH	NM_145071.4	c.428A>G	p.Asn143Ser	missense_variant	3/3	ENST00000348721.4
CISH	NM_013324.7	c.479A>G	p.Asn160Ser	missense_variant	4/4
CISH	XM_047447398.1	c.479A>G	p.Asn160Ser	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CISH	ENST00000348721.4	c.428A>G	p.Asn143Ser	missense_variant	3/3	1	NM_145071.4	P1
CISH	ENST00000443053.6	c.479A>G	p.Asn160Ser	missense_variant	4/4	1
CISH	ENST00000491847.1	n.3576A>G		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000167 AC: 42 AN: 251088 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135840

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000316 AC: 462 AN: 1461726 Hom.: 0 Cov.: 32 AF XY: 0.000289 AC XY: 210 AN XY: 727162

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000367

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74436

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000238 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000436

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

The c.479A>G (p.N160S) alteration is located in exon 4 (coding exon 3) of the CISH gene. This alteration results from a A to G substitution at nucleotide position 479, causing the asparagine (N) at amino acid position 160 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	0.10
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	18
Dann	Benign	0.83
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T;D
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.046	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.23	N;N
REVEL	Benign	0.10
Sift	Benign	0.57	T;T
Sift4G	Benign	0.93	T;T
Polyphen		0.083	.;B
Vest4		0.052
MVP		0.39
MPC		0.25
ClinPred		0.024	T
GERP RS		4.5
Varity_R		0.067
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145827559; hg19: chr3-50645387;