chr8-33509885-G-C

Variant names:

• chr8-33509885-G-C
• rs369757546
• NM_001102401.4:c.695C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001102401.4(TTI2):​c.695C>G​(p.Thr232Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000075 in 1,600,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T232I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: TTI2 NM_001102401.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.55
• Publications: 0 publications found

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]

TTI2 Gene-Disease associations (from GenCC):

• severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.103093).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001102401.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTI2	NM_001102401.4	MANE Select	c.695C>G	p.Thr232Ser	missense	Exon 3 of 8	NP_001095871.1
	TTI2	NM_001265581.2		c.695C>G	p.Thr232Ser	missense	Exon 3 of 8	NP_001252510.1
	TTI2	NM_025115.5		c.695C>G	p.Thr232Ser	missense	Exon 2 of 7	NP_079391.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTI2	ENST00000431156.7	TSL:1 MANE Select	c.695C>G	p.Thr232Ser	missense	Exon 3 of 8	ENSP00000411169.3
	TTI2	ENST00000613904.1	TSL:1	c.695C>G	p.Thr232Ser	missense	Exon 3 of 8	ENSP00000478396.1
	TTI2	ENST00000360742.9	TSL:2	c.695C>G	p.Thr232Ser	missense	Exon 2 of 7	ENSP00000353971.5

Frequencies

GnomAD3 genomes AF: 0.0000200 AC: 3 AN: 150052 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000601

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

GnomAD2 exomes AF: 0.0000437 AC: 11 AN: 251460 AF XY: 0.0000441

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000620 AC: 9 AN: 1450910 Hom.: 0 Cov.: 33 AF XY: 0.00000693 AC XY: 5 AN XY: 721842

African (AFR) AF: 0.00 AC: 0 AN: 33064

American (AMR) AF: 0.00 AC: 0 AN: 44288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25666

East Asian (EAS) AF: 0.000231 AC: 9 AN: 38884

South Asian (SAS) AF: 0.00 AC: 0 AN: 86138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105206

Other (OTH) AF: 0.00 AC: 0 AN: 59608

GnomAD4 genome AF: 0.0000200 AC: 3 AN: 150052 Hom.: 0 Cov.: 30 AF XY: 0.0000411 AC XY: 3 AN XY: 73008

African (AFR) AF: 0.00 AC: 0 AN: 40760

American (AMR) AF: 0.00 AC: 0 AN: 14922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.000601 AC: 3 AN: 4994

South Asian (SAS) AF: 0.00 AC: 0 AN: 4692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67746

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000576 AC: 7

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.034
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.6
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.18
Sift	Benign	0.099	T
Sift4G	Benign	0.12	T
Polyphen		0.11	B
Vest4		0.32
MutPred		0.65		Loss of helix (P = 0.0376)
MVP		0.28
MPC		0.19
ClinPred		0.042	T
GERP RS		3.1
Varity_R		0.051
gMVP		0.20
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs369757546; hg19: chr8-33367403;