17-61869099-T-C

Position:

• chr17-61869099-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001351695.2(INTS2):​c.3179A>G​(p.Tyr1060Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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: 7.42

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INTS2	NM_001351695.2	c.3179A>G	p.Tyr1060Cys	missense_variant	23/25	ENST00000251334.7	NP_001338624.2
INTS2	NM_020748.4	c.3203A>G	p.Tyr1068Cys	missense_variant	23/25		NP_065799.2
INTS2	NM_001330417.2	c.3179A>G	p.Tyr1060Cys	missense_variant	23/25		NP_001317346.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INTS2	ENST00000251334.7	c.3179A>G	p.Tyr1060Cys	missense_variant	23/25	2	NM_001351695.2	ENSP00000251334.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

May 21, 2024

The c.3203A>G (p.Y1068C) alteration is located in exon 23 (coding exon 23) of the INTS2 gene. This alteration results from a A to G substitution at nucleotide position 3203, causing the tyrosine (Y) at amino acid position 1068 to be replaced by a cysteine (C). 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	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;T;T
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;.;.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.5	M;M;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.9	.;D;.;.
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	.;D;.;.
Sift4G	Pathogenic	0.0010	D;D;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.93
MutPred		0.59		Gain of ubiquitination at K1072 (P = 0.0882);Gain of ubiquitination at K1072 (P = 0.0882);.;.;
MVP		0.63
MPC		0.69
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.94
gMVP		0.85

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: chr17-59946460;