13-19464518-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001395978.1(TPTE2):​c.679C>T​(p.Arg227Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000479 in 1,611,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00048 ( 0 hom. )

Consequence

TPTE2
NM_001395978.1 missense, splice_region

Scores

5
4
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.66
Variant links:
Genes affected
TPTE2 (HGNC:17299): (transmembrane phosphoinositide 3-phosphatase and tensin homolog 2) TPIP is a member of a large class of membrane-associated phosphatases with substrate specificity for the 3-position phosphate of inositol phospholipids.[supplied by OMIM, Jul 2002]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2844718).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TPTE2NM_001395978.1 linkuse as main transcriptc.679C>T p.Arg227Cys missense_variant, splice_region_variant 13/23 ENST00000697147.1 NP_001382907.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TPTE2ENST00000697147.1 linkuse as main transcriptc.679C>T p.Arg227Cys missense_variant, splice_region_variant 13/23 NM_001395978.1 ENSP00000513136 P2Q6XPS3-1

Frequencies

GnomAD3 genomes
AF:
0.000487
AC:
74
AN:
152004
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000941
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000322
AC:
80
AN:
248568
Hom.:
0
AF XY:
0.000343
AC XY:
46
AN XY:
134306
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000296
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000101
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000550
Gnomad OTH exome
AF:
0.000329
GnomAD4 exome
AF:
0.000478
AC:
698
AN:
1459782
Hom.:
0
Cov.:
32
AF XY:
0.000446
AC XY:
324
AN XY:
726192
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.000203
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000105
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000586
Gnomad4 OTH exome
AF:
0.000414
GnomAD4 genome
AF:
0.000486
AC:
74
AN:
152122
Hom.:
0
Cov.:
32
AF XY:
0.000444
AC XY:
33
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000941
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000638
Hom.:
0
Bravo
AF:
0.000453
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000280
AC:
34

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 16, 2023The c.679C>T (p.R227C) alteration is located in exon 11 (coding exon 10) of the TPTE2 gene. This alteration results from a C to T substitution at nucleotide position 679, causing the arginine (R) at amino acid position 227 to be replaced by a cysteine (C). 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
0.31
BayesDel_addAF
Uncertain
0.065
T
BayesDel_noAF
Pathogenic
0.25
CADD
Benign
22
DANN
Benign
0.90
DEOGEN2
Uncertain
0.71
.;D;.;.;.
Eigen
Benign
-0.44
Eigen_PC
Benign
-0.60
FATHMM_MKL
Benign
0.27
N
LIST_S2
Uncertain
0.87
D;D;D;D;.
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.28
T;T;T;T;T
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Pathogenic
4.0
.;H;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
PrimateAI
Benign
0.41
T
PROVEAN
Pathogenic
-6.1
D;D;D;D;D
REVEL
Pathogenic
0.67
Sift
Benign
0.041
D;D;D;T;D
Sift4G
Uncertain
0.021
D;D;D;D;D
Polyphen
0.15, 0.23
.;B;B;.;B
Vest4
0.57
MVP
0.77
MPC
0.41
ClinPred
0.12
T
GERP RS
1.7
Varity_R
0.21
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs148045725; hg19: chr13-20038658; COSMIC: COSV99689643; API