chr2-218584683-C-T

Variant names:

• chr2-218584683-C-T
• rs267599211
• NM_005444.3:c.392C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_005444.3(CNOT9):​c.392C>T​(p.Pro131Leu) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNOT9 NM_005444.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.75
• Publications: 16 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: Likely_pathogenic. The variant received 7 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, 0.876
• PP5: Variant 2-218584683-C-T is Pathogenic according to our data. Variant chr2-218584683-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 74445.Status of the report is criteria_provided_single_submitter, 1 stars.

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.392C>T	p.Pro131Leu	missense	Exon 4 of 8	NP_005435.1	Q92600-1
	CNOT9	NM_001271634.2		c.392C>T	p.Pro131Leu	missense	Exon 4 of 9	NP_001258563.1	Q92600-2
	CNOT9	NM_001271635.2		c.392C>T	p.Pro131Leu	missense	Exon 4 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.392C>T	p.Pro131Leu	missense	Exon 4 of 8	ENSP00000273064.6	Q92600-1
	CNOT9	ENST00000295701.9	TSL:1	c.392C>T	p.Pro131Leu	missense	Exon 4 of 8	ENSP00000295701.5	Q92600-3
	CNOT9	ENST00000627282.2	TSL:2	c.392C>T	p.Pro131Leu	missense	Exon 4 of 9	ENSP00000486540.1	Q92600-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	CNOT9-associated neurodevelopmental disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.19	D
PhyloP100		7.7
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-8.2	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.59		Loss of methylation at K128 (P = 0.0644)
MVP		0.74
MPC		2.3
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.86
gMVP		0.71
Mutation Taster		=12/88	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267599211; hg19: chr2-219449406; COSMIC: COSV55298957; COSMIC: COSV55298957;