17-61867702-G-C

Variant names:

• chr17-61867702-G-C
• rs1435588310
• NM_001351695.2:c.3446C>G

Variant summary

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

The NM_001351695.2(INTS2):​c.3446C>G​(p.Pro1149Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000197 in 151,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 32)
• Consequence: INTS2 NM_001351695.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.90

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14001971).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INTS2	NM_001351695.2	c.3446C>G	p.Pro1149Arg	missense_variant	Exon 25 of 25	ENST00000251334.7	NP_001338624.2
INTS2	NM_020748.4	c.3470C>G	p.Pro1157Arg	missense_variant	Exon 25 of 25		NP_065799.2
INTS2	NM_001330417.2	c.3446C>G	p.Pro1149Arg	missense_variant	Exon 25 of 25		NP_001317346.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INTS2	ENST00000251334.7	c.3446C>G	p.Pro1149Arg	missense_variant	Exon 25 of 25	2	NM_001351695.2	ENSP00000251334.6

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151954 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151954 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74236

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3470C>G (p.P1157R) alteration is located in exon 25 (coding exon 25) of the INTS2 gene. This alteration results from a C to G substitution at nucleotide position 3470, causing the proline (P) at amino acid position 1157 to be replaced by an arginine (R). 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	Benign	0.18
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Benign	0.043	T;T;T;T
Eigen	Benign	0.096
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T;.;.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.4	.;N;.;.
REVEL	Benign	0.063
Sift	Benign	0.048	.;D;.;.
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		0.0	B;B;.;.
Vest4		0.18
MutPred		0.26		Gain of MoRF binding (P = 0.004);Gain of MoRF binding (P = 0.004);.;.;
MVP		0.15
MPC		0.28
ClinPred		0.92	D
GERP RS		4.9
Varity_R		0.28
gMVP		0.75

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: rs1435588310; hg19: chr17-59945063;