chr2-218584682-C-T

Position:

• chr2-218584682-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

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).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNOT9 NM_005444.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.75

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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	Protein	UniProt
CNOT9	NM_005444.3	c.391C>T	p.Pro131Ser	missense_variant	4/8	ENST00000273064.11	NP_005435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNOT9	ENST00000273064.11	c.391C>T	p.Pro131Ser	missense_variant	4/8	1	NM_005444.3	ENSP00000273064	P1
CNOT9	ENST00000295701.9	c.391C>T	p.Pro131Ser	missense_variant	4/8	1		ENSP00000295701
CNOT9	ENST00000627282.2	c.391C>T	p.Pro131Ser	missense_variant	4/9	2		ENSP00000486540
CNOT9	ENST00000432877.5			downstream_gene_variant		3		ENSP00000392394

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

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

- -

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

Other links and lift over

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