rs1559931

Variant names:

• chr2-203961006-G-A
• rs1559931
• NM_012092.4:c.*1407G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-203961006-G-A
• chr2-203961006-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012092.4(ICOS):​c.*1407G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 152,020 control chromosomes in the GnomAD database, including 7,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7033 hom., cov: 32)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: ICOS NM_012092.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.477
• Publications: 25 publications found

Genes affected

ICOS (HGNC:5351): (inducible T cell costimulator) The protein encoded by this gene belongs to the CD28 and CTLA-4 cell-surface receptor family. It forms homodimers and plays an important role in cell-cell signaling, immune responses, and regulation of cell proliferation. [provided by RefSeq, Jul 2008]

ICOS Gene-Disease associations (from GenCC):

• common variable immunodeficiency

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• immunodeficiency, common variable, 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 2-203961006-G-A is Benign according to our data. Variant chr2-203961006-G-A is described in ClinVar as Benign. ClinVar VariationId is 333759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ICOS	NM_012092.4	c.*1407G>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000316386.11	NP_036224.1
ICOS	XR_007073112.1	n.2172G>A		non_coding_transcript_exon_variant	Exon 6 of 6
ICOS	XM_047444022.1	c.*1407G>A		3_prime_UTR_variant	Exon 5 of 5		XP_047299978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICOS	ENST00000316386.11	c.*1407G>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_012092.4	ENSP00000319476.6
ICOS	ENST00000435193.1	c.*1415G>A		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000415951.1

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44134 AN: 151894 Hom.: 7000 Cov.: 32

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.285

GnomAD4 exome AF: 0.250 AC: 2 AN: 8 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.167 AC: 1 AN: 6

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.291 AC: 44223 AN: 152012 Hom.: 7033 Cov.: 32 AF XY: 0.291 AC XY: 21599 AN XY: 74300

African (AFR) AF: 0.409 AC: 16947 AN: 41416

American (AMR) AF: 0.288 AC: 4403 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 781 AN: 3470

East Asian (EAS) AF: 0.197 AC: 1020 AN: 5168

South Asian (SAS) AF: 0.339 AC: 1632 AN: 4820

European-Finnish (FIN) AF: 0.227 AC: 2399 AN: 10566

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.238 AC: 16175 AN: 67972

Other (OTH) AF: 0.291 AC: 614 AN: 2112

Alfa AF: 0.256 Hom.: 8602

Bravo AF: 0.297

Asia WGS AF: 0.306 AC: 1064 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 18, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25497975) -

Immunodeficiency, common variable, 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.40
DANN	Benign	0.33
PhyloP100		-0.48
Mutation Taster		=100/0	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: rs1559931; hg19: chr2-204825729;