2-203954258-T-A

Variant names:

• chr2-203954258-T-A
• rs12466129
• NM_012092.4:c.59-1378T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012092.4(ICOS):​c.59-1378T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 152,160 control chromosomes in the GnomAD database, including 2,683 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 0.17 (2683 hom., cov: 33)
• Consequence: ICOS NM_012092.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.236
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.226 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOS	NM_012092.4	MANE Select	c.59-1378T>A		intron	N/A	NP_036224.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOS	ENST00000316386.11	TSL:1 MANE Select	c.59-1378T>A		intron	N/A	ENSP00000319476.6
	ICOS	ENST00000435193.1	TSL:1	c.59-1378T>A		intron	N/A	ENSP00000415951.1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25912 AN: 152042 Hom.: 2673 Cov.: 33

Gnomad AFR AF: 0.0686

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.0908

Gnomad EAS AF: 0.0467

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.147

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.171 AC: 25948 AN: 152160 Hom.: 2683 Cov.: 33 AF XY: 0.167 AC XY: 12430 AN XY: 74372

African (AFR) AF: 0.0684 AC: 2844 AN: 41550

American (AMR) AF: 0.178 AC: 2714 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0908 AC: 315 AN: 3468

East Asian (EAS) AF: 0.0466 AC: 242 AN: 5190

South Asian (SAS) AF: 0.128 AC: 618 AN: 4830

European-Finnish (FIN) AF: 0.292 AC: 3073 AN: 10542

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.229 AC: 15592 AN: 67982

Other (OTH) AF: 0.154 AC: 325 AN: 2106

Alfa AF: 0.203 Hom.: 433

Bravo AF: 0.160

Asia WGS AF: 0.105 AC: 363 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.82
PhyloP100		-0.24
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: rs12466129; hg19: chr2-204818981;