NM_005444.3:c.259T>C

Variant names:

• chr2-218583025-T-C
• rs1057519956
• NM_005444.3:c.259T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CNOT9 NM_005444.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.2774 (above the threshold of 3.09). Trascript score misZ: 3.6816 (above the threshold of 3.09).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005444.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT9	NM_005444.3	MANE Select	c.259T>C	p.Ser87Pro	missense	Exon 3 of 8	NP_005435.1	Q92600-1
	CNOT9	NM_001271634.2		c.259T>C	p.Ser87Pro	missense	Exon 3 of 9	NP_001258563.1	Q92600-2
	CNOT9	NM_001271635.2		c.259T>C	p.Ser87Pro	missense	Exon 3 of 8	NP_001258564.1	Q92600-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT9	ENST00000273064.11	TSL:1 MANE Select	c.259T>C	p.Ser87Pro	missense	Exon 3 of 8	ENSP00000273064.6	Q92600-1
	CNOT9	ENST00000295701.9	TSL:1	c.259T>C	p.Ser87Pro	missense	Exon 3 of 8	ENSP00000295701.5	Q92600-3
	CNOT9	ENST00000627282.2	TSL:2	c.259T>C	p.Ser87Pro	missense	Exon 3 of 9	ENSP00000486540.1	Q92600-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.056	D
PhyloP100		8.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.74
Sift	Benign	0.034	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.75		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
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057519956; hg19: chr2-219447748; COSMIC: COSV55299564; COSMIC: COSV55299564;