rs77411896

Positions:

• chr2-203936854-C-A
• chr2-203936854-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000316386.11(ICOS):​c.40C>A​(p.Arg14Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,458,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R14C) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ICOS ENST00000316386.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.89

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]

LOC101927840 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13389078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ICOS	NM_012092.4	c.40C>A	p.Arg14Ser	missense_variant	1/5	ENST00000316386.11	NP_036224.1
LOC101927840	XR_427213.4	n.314+463G>T		intron_variant, non_coding_transcript_variant
ICOS	XR_007073112.1	n.92C>A		non_coding_transcript_exon_variant	1/6
ICOS	XM_047444022.1			upstream_gene_variant			XP_047299978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICOS	ENST00000316386.11	c.40C>A	p.Arg14Ser	missense_variant	1/5	1	NM_012092.4	ENSP00000319476	P2
ICOS	ENST00000435193.1	c.40C>A	p.Arg14Ser	missense_variant	1/4	1		ENSP00000415951	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458282 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4 AN XY: 725694

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	23
DANN	Benign	0.84
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.083
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.35	T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;N
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.14	N;N
REVEL	Benign	0.11
Sift	Benign	0.13	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.0	B;B
Vest4		0.27
MutPred		0.40		Loss of MoRF binding (P = 0.0444);Loss of MoRF binding (P = 0.0444);
MVP		0.27
MPC		0.38
ClinPred		0.39	T
GERP RS		5.6
Varity_R		0.14
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs77411896; hg19: chr2-204801577;