rs1057519956

Positions:

• chr2-218583025-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_005444.3(CNOT9):​c.259T>C​(p.Ser87Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. S87C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CNOT9 NM_005444.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:5
• Conservation: PhyloP100: 8.02

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 Likely_pathogenic. Variant got 9 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 chr2-218583026-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376527.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 2-218583025-T-C is Pathogenic according to our data. Variant chr2-218583025-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376526.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	c.259T>C	p.Ser87Pro	missense_variant	3/8	ENST00000273064.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNOT9	ENST00000273064.11	c.259T>C	p.Ser87Pro	missense_variant	3/8	1	NM_005444.3	P1
CNOT9	ENST00000295701.9	c.259T>C	p.Ser87Pro	missense_variant	3/8	1
CNOT9	ENST00000627282.2	c.259T>C	p.Ser87Pro	missense_variant	3/9	2
CNOT9	ENST00000432877.5	c.*151T>C		3_prime_UTR_variant, NMD_transcript_variant	4/5	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: no assertion criteria provided

Submissions by phenotype

Prostate adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gastric adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Transitional cell carcinoma of the bladder Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant melanoma of skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Hepatocellular carcinoma 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	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;T;T;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.056	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.6	.;D;D;D
REVEL	Pathogenic	0.74
Sift	Benign	0.034	.;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.89
MutPred		0.75		Loss of glycosylation at S87 (P = 0.0588);Loss of glycosylation at S87 (P = 0.0588);Loss of glycosylation at S87 (P = 0.0588);Loss of glycosylation at S87 (P = 0.0588);
MVP		0.73
MPC		2.6
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.96
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1057519956; hg19: chr2-219447748; COSMIC: COSV55299564; COSMIC: COSV55299564;