rs1057519955

Variant names:

• chr2-218584682-C-T
• rs1057519955
• NM_005444.3:c.391C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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
• 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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain CCR4-NOT transcription complex subunit 9 (size 298) in uniprot entity CNOT9_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT9	NM_005444.3	c.391C>T	p.Pro131Ser	missense_variant	Exon 4 of 8	ENST00000273064.11	NP_005435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT9	ENST00000273064.11	c.391C>T	p.Pro131Ser	missense_variant	Exon 4 of 8	1	NM_005444.3	ENSP00000273064.6
CNOT9	ENST00000295701.9	c.391C>T	p.Pro131Ser	missense_variant	Exon 4 of 8	1		ENSP00000295701.5
CNOT9	ENST00000627282.2	c.391C>T	p.Pro131Ser	missense_variant	Exon 4 of 9	2		ENSP00000486540.1
CNOT9	ENST00000432877.5	n.*283C>T		downstream_gene_variant		3		ENSP00000392394.1

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

May 31, 2016

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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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
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;