X-100824151-C-T

Variant summary

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

The NM_001325.3(CSTF2):​c.596C>T​(p.Thr199Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000413 in 1,210,327 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T199A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 24)
Exomes 𝑓: 0.0000036 ( 0 hom. 0 hem. )

Consequence

CSTF2
NM_001325.3 missense

Scores

1
6
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.19
Variant links:
Genes affected
CSTF2 (HGNC:2484): (cleavage stimulation factor subunit 2) This gene encodes a nuclear protein with an RRM (RNA recognition motif) domain. The protein is a member of the cleavage stimulation factor (CSTF) complex that is involved in the 3' end cleavage and polyadenylation of pre-mRNAs. Specifically, this protein binds GU-rich elements within the 3'-untranslated region of mRNAs. [provided by RefSeq, Jul 2008]

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=0.26929933).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CSTF2NM_001325.3 linkc.596C>T p.Thr199Met missense_variant Exon 6 of 14 ENST00000372972.7 NP_001316.1 P33240-1
CSTF2NM_001306206.2 linkc.596C>T p.Thr199Met missense_variant Exon 6 of 15 NP_001293135.1 E7EWR4B3V096B4DUD5
CSTF2NM_001306209.2 linkc.596C>T p.Thr199Met missense_variant Exon 6 of 14 NP_001293138.1 P33240-2B4DUD5
CSTF2XM_047441854.1 linkc.596C>T p.Thr199Met missense_variant Exon 6 of 10 XP_047297810.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CSTF2ENST00000372972.7 linkc.596C>T p.Thr199Met missense_variant Exon 6 of 14 1 NM_001325.3 ENSP00000362063.2 P33240-1
CSTF2ENST00000415585.7 linkc.596C>T p.Thr199Met missense_variant Exon 6 of 15 1 ENSP00000387996.2 E7EWR4
CSTF2ENST00000413437.1 linkc.569C>T p.Thr190Met missense_variant Exon 6 of 6 5 ENSP00000415705.1 A0A0A0MT56
CSTF2ENST00000475126.5 linkn.596C>T non_coding_transcript_exon_variant Exon 6 of 14 5 ENSP00000432060.1 E9PID8

Frequencies

GnomAD3 genomes
AF:
0.00000890
AC:
1
AN:
112348
Hom.:
0
Cov.:
24
AF XY:
0.00
AC XY:
0
AN XY:
34506
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:
0.0000188
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000219
AC:
4
AN:
182981
Hom.:
0
AF XY:
0.0000148
AC XY:
1
AN XY:
67435
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000217
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000122
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000364
AC:
4
AN:
1097979
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
363345
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000662
Gnomad4 SAS exome
AF:
0.0000185
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000119
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000890
AC:
1
AN:
112348
Hom.:
0
Cov.:
24
AF XY:
0.00
AC XY:
0
AN XY:
34506
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000188
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 02, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.596C>T (p.T199M) alteration is located in exon 6 (coding exon 6) of the CSTF2 gene. This alteration results from a C to T substitution at nucleotide position 596, causing the threonine (T) at amino acid position 199 to be replaced by a methionine (M). 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
0.15
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.68
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.048
.;T;T
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Uncertain
0.27
D
MetaRNN
Benign
0.27
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.4
.;L;.
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-1.7
N;N;N
REVEL
Benign
0.096
Sift
Uncertain
0.0030
D;D;D
Sift4G
Uncertain
0.019
D;D;D
Polyphen
0.15
B;B;.
Vest4
0.21
MutPred
0.36
Loss of glycosylation at T199 (P = 0.0408);Loss of glycosylation at T199 (P = 0.0408);.;
MVP
0.63
MPC
1.4
ClinPred
0.37
T
GERP RS
5.6
Varity_R
0.42
gMVP
0.17

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs769877951; hg19: chrX-100079140; COSMIC: COSV63376139; COSMIC: COSV63376139; API