2-218584682-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP5

The NM_005444.3(CNOT9):​c.391C>T​(p.Pro131Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P131L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CNOT9
NM_005444.3 missense

Scores

4
8
6

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.75
Variant links:
Genes affected
CNOT9 (HGNC:10445): (CCR4-NOT transcription complex subunit 9) This gene encodes a member of the highly conserved RCD1 protein family. The encoded protein is a transcriptional cofactor and a core protein of the CCR4-NOT complex. It may be involved in signal transduction as well as retinoic acid-regulated cell differentiation and development. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Oct 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a chain CCR4-NOT transcription complex subunit 9 (size 298) in uniprot entity CNOT9_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_005444.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-218584683-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 74445.Status of the report is criteria_provided_single_submitter, 1 stars.
PP5
Variant 2-218584682-C-T is Pathogenic according to our data. Variant chr2-218584682-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376525.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CNOT9NM_005444.3 linkuse as main transcriptc.391C>T p.Pro131Ser missense_variant 4/8 ENST00000273064.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CNOT9ENST00000273064.11 linkuse as main transcriptc.391C>T p.Pro131Ser missense_variant 4/81 NM_005444.3 P1Q92600-1
CNOT9ENST00000295701.9 linkuse as main transcriptc.391C>T p.Pro131Ser missense_variant 4/81 Q92600-3
CNOT9ENST00000627282.2 linkuse as main transcriptc.391C>T p.Pro131Ser missense_variant 4/92 Q92600-2
CNOT9ENST00000432877.5 linkuse as main transcript downstream_gene_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Malignant melanoma of skin Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.28
.;T;T;.
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.98
D;.;D;D
M_CAP
Benign
0.016
T
MetaRNN
Uncertain
0.56
D;D;D;D
MetaSVM
Benign
-0.87
T
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-6.0
.;D;D;D
REVEL
Uncertain
0.30
Sift
Benign
0.16
.;T;T;T
Sift4G
Benign
0.17
T;T;T;T
Polyphen
0.39
.;B;B;.
Vest4
0.70
MutPred
0.51
Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP
0.37
MPC
1.4
ClinPred
0.96
D
GERP RS
5.2
Varity_R
0.63
gMVP
0.60

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: rs1057519955; hg19: chr2-219449405; COSMIC: COSV55299045; COSMIC: COSV55299045; API