5-180564741-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001370472.1(CNOT6):​c.557C>T​(p.Thr186Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000657 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

CNOT6
NM_001370472.1 missense, splice_region

Scores

2
1
16
Splicing: ADA: 0.9257
1
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.16
Variant links:
Genes affected
CNOT6 (HGNC:14099): (CCR4-NOT transcription complex subunit 6) This gene encodes the catalytic component of the CCR4-NOT core transcriptional regulation complex. The encoded protein has a 3'-5' RNase activity and prefers polyadenylated substrates. The CCR4-NOT complex plays a role in many cellular processes, including miRNA-mediated repression, mRNA degradation, and transcriptional regulation. [provided by RefSeq, Dec 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.19165239).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CNOT6NM_001370472.1 linkuse as main transcriptc.557C>T p.Thr186Ile missense_variant, splice_region_variant 6/12 ENST00000261951.9 NP_001357401.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CNOT6ENST00000261951.9 linkuse as main transcriptc.557C>T p.Thr186Ile missense_variant, splice_region_variant 6/125 NM_001370472.1 ENSP00000261951 P1
CNOT6ENST00000393356.7 linkuse as main transcriptc.557C>T p.Thr186Ile missense_variant, splice_region_variant 8/141 ENSP00000377024 P1
CNOT6ENST00000618123.4 linkuse as main transcriptc.557C>T p.Thr186Ile missense_variant, splice_region_variant 7/131 ENSP00000481893 P1
CNOT6ENST00000504343.1 linkuse as main transcriptc.269C>T p.Thr90Ile missense_variant, splice_region_variant 3/63 ENSP00000422087

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152196
Hom.:
0
Cov.:
33
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251168
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135750
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
30
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152196
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000113
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1

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 GeneticsJul 30, 2023The c.557C>T (p.T186I) alteration is located in exon 6 (coding exon 5) of the CNOT6 gene. This alteration results from a C to T substitution at nucleotide position 557, causing the threonine (T) at amino acid position 186 to be replaced by an isoleucine (I). 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
0.24
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.37
CADD
Uncertain
25
DANN
Benign
0.93
DEOGEN2
Benign
0.060
T;T;T;T
Eigen
Benign
0.033
Eigen_PC
Benign
0.21
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.93
D;.;.;D
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.19
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.76
N;N;N;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-1.9
N;N;.;N
REVEL
Benign
0.087
Sift
Benign
0.28
T;T;.;T
Sift4G
Benign
0.35
T;T;T;T
Polyphen
0.015
B;B;B;B
Vest4
0.42
MVP
0.50
MPC
0.65
ClinPred
0.36
T
GERP RS
5.3
Varity_R
0.18
gMVP
0.39

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.93
dbscSNV1_RF
Pathogenic
0.78
SpliceAI score (max)
0.050
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: rs373787258; hg19: chr5-179991741; API