17-61869139-T-G

Position:

• chr17-61869139-T-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.3139A>C​(p.Ile1047Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000279 in 1,431,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: INTS2 NM_001351695.2 missense, splice_region
• Scores: Splicing: ADA: 0.05783
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.58

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=0.23695588).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INTS2	NM_001351695.2	c.3139A>C	p.Ile1047Leu	missense_variant, splice_region_variant	23/25	ENST00000251334.7	NP_001338624.2
INTS2	NM_020748.4	c.3163A>C	p.Ile1055Leu	missense_variant, splice_region_variant	23/25		NP_065799.2
INTS2	NM_001330417.2	c.3139A>C	p.Ile1047Leu	missense_variant, splice_region_variant	23/25		NP_001317346.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INTS2	ENST00000251334.7	c.3139A>C	p.Ile1047Leu	missense_variant, splice_region_variant	23/25	2	NM_001351695.2	ENSP00000251334.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1431598 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 713730

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000368

Gnomad4 OTH exome AF: 0.00

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

Feb 15, 2023

The c.3163A>C (p.I1055L) alteration is located in exon 23 (coding exon 23) of the INTS2 gene. This alteration results from a A to C substitution at nucleotide position 3163, causing the isoleucine (I) at amino acid position 1055 to be replaced by a leucine (L). 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	0.29
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.059	T;T;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;.;.;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.2	.;N;.;.
REVEL	Benign	0.092
Sift	Benign	0.42	.;T;.;.
Sift4G	Benign	0.41	T;T;.;T
Polyphen		0.0	B;B;.;.
Vest4		0.66
MutPred		0.23		Loss of catalytic residue at L1060 (P = 0.0276);Loss of catalytic residue at L1060 (P = 0.0276);.;.;
MVP		0.20
MPC		0.27
ClinPred		0.74	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.058
dbscSNV1_RF	Benign	0.17
SpliceAI score (max)		0.050		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: chr17-59946500;