Variant chr2-218584682-C-T details in Genebe, Genetics Data Aggregator

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

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]

CNOT9 links:

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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
CNOT9	NM_005444.3 linkuse as main transcript	c.391C>T	p.Pro131Ser	missense_variant	4/8	ENST00000273064.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNOT9	ENST00000273064.11 linkuse as main transcript	c.391C>T	p.Pro131Ser	missense_variant	4/8	1	NM_005444.3	P1	Q92600-1
CNOT9	ENST00000295701.9 linkuse as main transcript	c.391C>T	p.Pro131Ser	missense_variant	4/8	1			Q92600-3
CNOT9	ENST00000627282.2 linkuse as main transcript	c.391C>T	p.Pro131Ser	missense_variant	4/9	2			Q92600-2
CNOT9	ENST00000432877.5 linkuse as main transcript			downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

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 provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

.;T;T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;.;D;D

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.56

D;D;D;D

MetaSVM

Benign

-0.87

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.90

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over