rs186443359

chr8-33512033-C-Gchr8-33512033-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001102401.4(TTI2):c.581G>C(p.Gly194Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000481 in 1,614,148 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (7 hom.)
• Consequence: TTI2 NM_001102401.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.07

Genes affected

TTI2 (HGNC:26262): (TELO2 interacting protein 2) This gene encodes a regulator of the DNA damage response. The protein is a component of the Triple T complex (TTT) which also includes telomere length regulation protein and TELO2 interacting protein 1. The TTT complex is involved in cellular resistance to DNA damage stresses and may act as a regulator of phosphoinositide-3-kinase-related protein kinase (PIKK) abundance. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068973005).
• BP6: Variant 8-33512033-C-G is Benign according to our data. Variant chr8-33512033-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 445746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTI2	NM_001102401.4	c.581G>C	p.Gly194Ala	missense_variant	2/8	ENST00000431156.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTI2	ENST00000431156.7	c.581G>C	p.Gly194Ala	missense_variant	2/8	1	NM_001102401.4	P1
TTI2	ENST00000613904.1	c.581G>C	p.Gly194Ala	missense_variant	2/8	1		P1
TTI2	ENST00000360742.9	c.581G>C	p.Gly194Ala	missense_variant	1/7	2		P1
TTI2	ENST00000520636.5	c.581G>C	p.Gly194Ala	missense_variant	1/6	5

Frequencies

GnomAD3 genomes AF: 0.000697 AC: 106 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00198 AC: 499 AN: 251488 Hom.: 4 AF XY: 0.00138 AC XY: 187 AN XY: 135918

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.000459 AC: 671 AN: 1461882 Hom.: 7 Cov.: 30 AF XY: 0.000367 AC XY: 267 AN XY: 727240

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0141

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: 0.00000629

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.000690 AC: 105 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74466

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00595

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0000908 Hom.: 1

Bravo AF: 0.00142

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00164 AC: 199

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T;T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.87	D;.;.;D
MetaRNN	Benign	0.0069	T;T;T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.8	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.40	T
Sift4G	Uncertain	0.024	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.68
MVP		0.67
MPC		0.65
ClinPred		0.041	T
GERP RS		4.7
Varity_R		0.15
gMVP		0.62

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: rs186443359; hg19: chr8-33369551;