dbSNP rs369656775: TELO2:p.Pro260Leu (chr16-1497457-C-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_016111.4(TELO2):c.779C>T(p.Pro260Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000699 in 1,572,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P260P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Consequence

TELO2
NM_016111.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 6.21

Publications

4 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 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.925

PP5

Variant 16-1497457-C-T is Pathogenic according to our data. Variant chr16-1497457-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 236228.

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.779C>T	p.Pro260Leu	missense	Exon 5 of 21	NP_057195.2	Q9Y4R8
	TELO2	NM_001351846.2		c.779C>T	p.Pro260Leu	missense	Exon 5 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.779C>T	p.Pro260Leu	missense	Exon 5 of 21	ENSP00000262319.6	Q9Y4R8
TELO2	ENST00000889741.1		c.779C>T	p.Pro260Leu	missense	Exon 5 of 21	ENSP00000559800.1
TELO2	ENST00000914530.1		c.779C>T	p.Pro260Leu	missense	Exon 5 of 21	ENSP00000584589.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000545

AC:

AN:

183366

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000129

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000704

AC:

AN:

1420536

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

703258

show subpopulations

African (AFR)

AF:

0.0000309

AC:

AN:

32334

American (AMR)

AF:

0.00

AC:

AN:

38772

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25422

East Asian (EAS)

AF:

0.00

AC:

AN:

37150

South Asian (SAS)

AF:

0.00

AC:

AN:

80978

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.00000824

AC:

AN:

1092816

Other (OTH)

AF:

0.00

AC:

AN:

58856

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:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

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 (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.63

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.44

MutationAssessor

Uncertain

2.8

PhyloP100

6.2

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.93

MVP

0.90

MPC

0.57

ClinPred

0.99

GERP RS

4.5

Varity_R

0.48

gMVP

0.59

Mutation Taster

=74/26

disease causing (ClinVar)

(source)

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

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