rs140049646

Variant names:

• chr2-203936881-T-G
• rs140049646
• NM_012092.4:c.58+9T>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_012092.4(ICOS):​c.58+9T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000647 in 1,562,618 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (4 hom.)
• Consequence: ICOS NM_012092.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.0300
• Publications: 0 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

ENSG00000300710 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-203936881-T-G is Benign according to our data. Variant chr2-203936881-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 333732.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0033 (503/152266) while in subpopulation AFR AF = 0.0112 (465/41550). AF 95% confidence interval is 0.0104. There are 3 homozygotes in GnomAd4. There are 217 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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.58+9T>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.58+9T>G		intron	N/A	ENSP00000319476.6	Q9Y6W8-1
	ICOS	ENST00000435193.1	TSL:1	c.58+9T>G		intron	N/A	ENSP00000415951.1	Q9Y6W8-2
	ICOS	ENST00000897354.1		c.58+9T>G		intron	N/A	ENSP00000567413.1

Frequencies

GnomAD3 genomes AF: 0.00329 AC: 501 AN: 152148 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000932 AC: 233 AN: 250090 AF XY: 0.000621

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.000637

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000360 AC: 508 AN: 1410352 Hom.: 4 Cov.: 24 AF XY: 0.000321 AC XY: 226 AN XY: 704980

African (AFR) AF: 0.0124 AC: 402 AN: 32384

American (AMR) AF: 0.000806 AC: 36 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25826

East Asian (EAS) AF: 0.00 AC: 0 AN: 39472

South Asian (SAS) AF: 0.0000821 AC: 7 AN: 85232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51806

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5688

European-Non Finnish (NFE) AF: 0.0000141 AC: 15 AN: 1066518

Other (OTH) AF: 0.000800 AC: 47 AN: 58760

GnomAD4 genome AF: 0.00330 AC: 503 AN: 152266 Hom.: 3 Cov.: 32 AF XY: 0.00291 AC XY: 217 AN XY: 74462

African (AFR) AF: 0.0112 AC: 465 AN: 41550

American (AMR) AF: 0.00183 AC: 28 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68020

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.00377

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Immunodeficiency, common variable, 1 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.7
DANN	Benign	0.45
PhyloP100		-0.030
PromoterAI		0.015	Neutral
Mutation Taster		=100/0	polymorphism

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: rs140049646; hg19: chr2-204801604;