rs753765

Positions:

• chr17-61891639-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001351695.2(INTS2):​c.1749A>G​(p.Gln583=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0779 in 1,612,594 control chromosomes in the GnomAD database, including 8,091 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.066 (587 hom., cov: 31)
  • Exomes 𝑓: 0.079 (7504 hom.)
• Consequence: INTS2 NM_001351695.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.314

Genes affected

INTS2 (HGNC:29241): (integrator complex subunit 2) INTS2 is a subunit of the Integrator complex, which associates with the C-terminal domain of RNA polymerase II large subunit (POLR2A; MIM 180660) and mediates 3-prime end processing of small nuclear RNAs U1 (RNU1; MIM 180680) and U2 (RNU2; MIM 180690) (Baillat et al., 2005 [PubMed 16239144]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 17-61891639-T-C is Benign according to our data. Variant chr17-61891639-T-C is described in ClinVar as [Benign]. Clinvar id is 3059600.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.314 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INTS2	NM_001351695.2	c.1749A>G	p.Gln583=	synonymous_variant	14/25	ENST00000251334.7
INTS2	NM_020748.4	c.1773A>G	p.Gln591=	synonymous_variant	14/25
INTS2	NM_001330417.2	c.1749A>G	p.Gln583=	synonymous_variant	14/25
INTS2	XR_934509.3	n.1815A>G		non_coding_transcript_exon_variant	14/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INTS2	ENST00000251334.7	c.1749A>G	p.Gln583=	synonymous_variant	14/25	2	NM_001351695.2	P1

Frequencies

GnomAD3 genomes AF: 0.0662 AC: 10065 AN: 152026 Hom.: 587 Cov.: 31

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.0549

Gnomad ASJ AF: 0.0816

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.0915

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0630

Gnomad OTH AF: 0.0603

GnomAD3 exomes AF: 0.105 AC: 26225 AN: 249050 Hom.: 2244 AF XY: 0.114 AC XY: 15363 AN XY: 135114

Gnomad AFR exome AF: 0.0171

Gnomad AMR exome AF: 0.0757

Gnomad ASJ exome AF: 0.0865

Gnomad EAS exome AF: 0.230

Gnomad SAS exome AF: 0.282

Gnomad FIN exome AF: 0.0920

Gnomad NFE exome AF: 0.0640

Gnomad OTH exome AF: 0.0835

GnomAD4 exome AF: 0.0792 AC: 115616 AN: 1460450 Hom.: 7504 Cov.: 30 AF XY: 0.0860 AC XY: 62488 AN XY: 726592

Gnomad4 AFR exome AF: 0.0154

Gnomad4 AMR exome AF: 0.0721

Gnomad4 ASJ exome AF: 0.0854

Gnomad4 EAS exome AF: 0.226

Gnomad4 SAS exome AF: 0.281

Gnomad4 FIN exome AF: 0.0876

Gnomad4 NFE exome AF: 0.0599

Gnomad4 OTH exome AF: 0.0803

GnomAD4 genome AF: 0.0662 AC: 10072 AN: 152144 Hom.: 587 Cov.: 31 AF XY: 0.0726 AC XY: 5401 AN XY: 74358

Gnomad4 AFR AF: 0.0176

Gnomad4 AMR AF: 0.0548

Gnomad4 ASJ AF: 0.0816

Gnomad4 EAS AF: 0.234

Gnomad4 SAS AF: 0.301

Gnomad4 FIN AF: 0.0915

Gnomad4 NFE AF: 0.0630

Gnomad4 OTH AF: 0.0620

Alfa AF: 0.0606 Hom.: 372

Bravo AF: 0.0564

Asia WGS AF: 0.232 AC: 806 AN: 3476

EpiCase AF: 0.0627

EpiControl AF: 0.0564

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

INTS2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.92
DANN	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs753765; hg19: chr17-59969000; COSMIC: COSV52150946;