chr2-203936881-T-G

Position:

• chr2-203936881-T-G

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id is 333732.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}. Variant chr2-203936881-T-G is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ICOS	NM_012092.4	c.58+9T>G		intron_variant		ENST00000316386.11
LOC101927840	XR_427213.4	n.314+436A>C		intron_variant, non_coding_transcript_variant
ICOS	XR_007073112.1	n.110+9T>G		intron_variant, non_coding_transcript_variant
ICOS	XM_047444022.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICOS	ENST00000316386.11	c.58+9T>G		intron_variant		1	NM_012092.4	P2
ICOS	ENST00000435193.1	c.58+9T>G		intron_variant		1		A2

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

GnomAD3 exomes AF: 0.000932 AC: 233 AN: 250090 Hom.: 4 AF XY: 0.000621 AC XY: 84 AN XY: 135340

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.000806

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000821

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000141

Gnomad4 OTH exome AF: 0.000800

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

Gnomad4 AFR AF: 0.0112

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.00377

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency, common variable, 1 Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.7
DANN	Benign	0.45

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: rs140049646; hg19: chr2-204801604;