Genetic Variant TELO2:p.Val766Met (chr16-1507605-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1PP5

The NM_016111.4(TELO2):c.2296G>A(p.Val766Met) variant causes a missense change. The variant allele was found at a frequency of 0.000111 in 1,588,212 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

TELO2
NM_016111.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:3

Conservation

PhyloP100: 5.73

Publications

3 publications found

Variant links:

Genes affected

TELO2 (HGNC:29099): (telomere maintenance 2) This gene encodes a protein that functions as an S-phase checkpoint protein in the cell cycle. The protein may also play a role in DNA repair.[provided by RefSeq, Mar 2009]

TELO2 Gene-Disease associations (from GenCC):

TELO2-related intellectual disability-neurodevelopmental disorder
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, PanelApp Australia

TELO2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_016111.4

PP5

Variant 16-1507605-G-A is Pathogenic according to our data. Variant chr16-1507605-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 236227.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016111.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TELO2	NM_016111.4	MANE Select	c.2296G>A	p.Val766Met	missense	Exon 20 of 21	NP_057195.2	Q9Y4R8
	TELO2	NM_001351846.2		c.2296G>A	p.Val766Met	missense	Exon 20 of 21	NP_001338775.1	Q9Y4R8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TELO2	ENST00000262319.11	TSL:1 MANE Select	c.2296G>A	p.Val766Met	missense	Exon 20 of 21	ENSP00000262319.6	Q9Y4R8
TELO2	ENST00000568240.1	TSL:1	n.588G>A		non_coding_transcript_exon	Exon 3 of 4
TELO2	ENST00000889741.1		c.2437G>A	p.Val813Met	missense	Exon 20 of 21	ENSP00000559800.1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000119

AC:

AN:

219280

AF XY:

0.000142

show subpopulations

Gnomad AFR exome

AF:

0.0000711

Gnomad AMR exome

AF:

0.0000928

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000989

Gnomad NFE exome

AF:

0.000195

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000113

AC:

162

AN:

1436056

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

713486

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33380

American (AMR)

AF:

0.0000698

AC:

AN:

42998

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25790

East Asian (EAS)

AF:

0.00

AC:

AN:

39260

South Asian (SAS)

AF:

0.0000119

AC:

AN:

84086

European-Finnish (FIN)

AF:

0.0000259

AC:

AN:

38554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.000140

AC:

155

AN:

1106498

Other (OTH)

AF:

0.0000167

AC:

AN:

59772

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000177

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000141

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

TELO2-related intellectual disability-neurodevelopmental disorder (4)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.83

M_CAP

Benign

0.048

MetaRNN

Uncertain

0.73

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.7

PhyloP100

5.7

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.30

Sift

Uncertain

0.021

Sift4G

Uncertain

0.043

Polyphen

0.99

Vest4

0.89

MVP

0.71

MPC

0.48

ClinPred

0.48

GERP RS

4.2

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.8

Varity_R

0.32

gMVP

0.67

Mutation Taster

=26/74

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over