17-61869782-T-G

Position:

• chr17-61869782-T-G

Variant summary

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

The NM_001351695.2(INTS2):​c.2985A>C​(p.Gln995His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: INTS2 NM_001351695.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0670

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INTS2	NM_001351695.2	c.2985A>C	p.Gln995His	missense_variant	21/25	ENST00000251334.7	NP_001338624.2
INTS2	NM_020748.4	c.3009A>C	p.Gln1003His	missense_variant	21/25		NP_065799.2
INTS2	NM_001330417.2	c.2985A>C	p.Gln995His	missense_variant	21/25		NP_001317346.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INTS2	ENST00000251334.7	c.2985A>C	p.Gln995His	missense_variant	21/25	2	NM_001351695.2	ENSP00000251334.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2024

The c.3009A>C (p.Q1003H) alteration is located in exon 21 (coding exon 21) of the INTS2 gene. This alteration results from a A to C substitution at nucleotide position 3009, causing the glutamine (Q) at amino acid position 1003 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;T;T;T
Eigen	Benign	0.024
Eigen_PC	Benign	-0.088
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.98	D;.;.;D
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.6	M;M;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.8	.;D;.;.
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	.;D;.;.
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		0.99	D;D;.;.
Vest4		0.95
MutPred		0.46		Gain of catalytic residue at Q1003 (P = 0.2442);Gain of catalytic residue at Q1003 (P = 0.2442);.;.;
MVP		0.94
MPC		0.89
ClinPred		1.0	D
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-59947143;