5-180565901-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001370472.1(CNOT6):​c.641C>T​(p.Ala214Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,562 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CNOT6
NM_001370472.1 missense

Scores

7
7
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.88
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 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CNOT6NM_001370472.1 linkc.641C>T p.Ala214Val missense_variant Exon 7 of 12 ENST00000261951.9 NP_001357401.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CNOT6ENST00000261951.9 linkc.641C>T p.Ala214Val missense_variant Exon 7 of 12 5 NM_001370472.1 ENSP00000261951.4 Q9ULM6
CNOT6ENST00000393356.7 linkc.641C>T p.Ala214Val missense_variant Exon 9 of 14 1 ENSP00000377024.1 Q9ULM6
CNOT6ENST00000618123.4 linkc.641C>T p.Ala214Val missense_variant Exon 8 of 13 1 ENSP00000481893.1 Q9ULM6
CNOT6ENST00000504343.1 linkc.353C>T p.Ala118Val missense_variant Exon 4 of 6 3 ENSP00000422087.1 D6R9H6

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251278
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135798
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1461562
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
727076
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000113
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
Nov 14, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.641C>T (p.A214V) alteration is located in exon 7 (coding exon 6) of the CNOT6 gene. This alteration results from a C to T substitution at nucleotide position 641, causing the alanine (A) at amino acid position 214 to be replaced by a valine (V). 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
Pathogenic
0.80
BayesDel_addAF
Uncertain
0.046
T
BayesDel_noAF
Benign
-0.11
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.57
D;D;D;D
Eigen
Uncertain
0.67
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D;.;.;D
M_CAP
Benign
0.020
T
MetaRNN
Pathogenic
0.92
D;D;D;D
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
2.0
M;M;M;.
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-3.1
D;D;.;D
REVEL
Uncertain
0.38
Sift
Uncertain
0.019
D;D;.;D
Sift4G
Uncertain
0.028
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.92
MutPred
0.86
Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);.;
MVP
0.39
MPC
1.4
ClinPred
0.94
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
0.98
Varity_R
0.42
gMVP
0.69

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

LitVar

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

Other links and lift over

dbSNP: rs763363186; hg19: chr5-179992901; COSMIC: COSV56159543; COSMIC: COSV56159543; API