rs10172036

Variant names:

• chr2-203959560-T-G
• rs10172036
• NM_012092.4:c.587-26T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-203959560-T-G
• chr2-203959560-T-A

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.587-26T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 1,600,854 control chromosomes in the GnomAD database, including 295,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.57 (25305 hom., cov: 30)
  • Exomes 𝑓: 0.61 (270647 hom.)
• Consequence: ICOS NM_012092.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.00600
• Publications: 12 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-203959560-T-G is Benign according to our data. Variant chr2-203959560-T-G is described in ClinVar as Benign. ClinVar VariationId is 1285249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.62 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012092.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOS	NM_012092.4	MANE Select	c.587-26T>G		intron	N/A	NP_036224.1	Q53QY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOS	ENST00000316386.11	TSL:1 MANE Select	c.587-26T>G		intron	N/A	ENSP00000319476.6	Q9Y6W8-1
	ICOS	ENST00000435193.1	TSL:1	c.502-26T>G		intron	N/A	ENSP00000415951.1	Q9Y6W8-2
	ICOS	ENST00000897354.1		c.251-26T>G		intron	N/A	ENSP00000567413.1

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87025 AN: 151682 Hom.: 25264 Cov.: 30

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.581

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.603

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.580

GnomAD2 exomes AF: 0.572 AC: 143554 AN: 250814 AF XY: 0.573

Gnomad AFR exome AF: 0.519

Gnomad AMR exome AF: 0.527

Gnomad ASJ exome AF: 0.593

Gnomad EAS exome AF: 0.448

Gnomad FIN exome AF: 0.598

Gnomad NFE exome AF: 0.624

Gnomad OTH exome AF: 0.590

GnomAD4 exome AF: 0.608 AC: 881373 AN: 1449054 Hom.: 270647 Cov.: 32 AF XY: 0.606 AC XY: 437012 AN XY: 721586

African (AFR) AF: 0.517 AC: 17062 AN: 33002

American (AMR) AF: 0.537 AC: 24000 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.598 AC: 15574 AN: 26058

East Asian (EAS) AF: 0.492 AC: 19493 AN: 39622

South Asian (SAS) AF: 0.509 AC: 43784 AN: 85940

European-Finnish (FIN) AF: 0.602 AC: 32139 AN: 53370

Middle Eastern (MID) AF: 0.585 AC: 3356 AN: 5738

European-Non Finnish (NFE) AF: 0.627 AC: 690590 AN: 1100702

Other (OTH) AF: 0.590 AC: 35375 AN: 59928

GnomAD4 genome AF: 0.574 AC: 87127 AN: 151800 Hom.: 25305 Cov.: 30 AF XY: 0.568 AC XY: 42085 AN XY: 74140

African (AFR) AF: 0.516 AC: 21335 AN: 41352

American (AMR) AF: 0.554 AC: 8453 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.581 AC: 2015 AN: 3468

East Asian (EAS) AF: 0.451 AC: 2325 AN: 5150

South Asian (SAS) AF: 0.492 AC: 2364 AN: 4800

European-Finnish (FIN) AF: 0.603 AC: 6341 AN: 10520

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.625 AC: 42447 AN: 67938

Other (OTH) AF: 0.584 AC: 1228 AN: 2102

Alfa AF: 0.603 Hom.: 36887

Bravo AF: 0.569

Asia WGS AF: 0.483 AC: 1681 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Immunodeficiency, common variable, 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.0
DANN	Benign	0.49
PhyloP100		-0.0060
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10172036; hg19: chr2-204824283; COSMIC: COSV57029174;