2-218594250-C-T

Variant names:

• chr2-218594250-C-T
• rs981210817
• NM_005444.3:c.874C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 11P and 1B. PM2 PP2 PP5_Very_Strong BP4

The NM_005444.3(CNOT9):​c.874C>T​(p.Arg292Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CNOT9 NM_005444.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.749
• Publications: 1 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: Pathogenic. The variant received 10 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).
• PP5: Variant 2-218594250-C-T is Pathogenic according to our data. Variant chr2-218594250-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1706475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31446582). . Strength limited to SUPPORTING due to the PP5.

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.874C>T	p.Arg292Trp	missense	Exon 8 of 8	NP_005435.1	Q92600-1
	CNOT9	NM_001271634.2		c.970C>T	p.Arg324Trp	missense	Exon 9 of 9	NP_001258563.1	Q92600-2
	CNOT9	NR_073390.2		n.880C>T		non_coding_transcript_exon	Exon 7 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT9	ENST00000273064.11	TSL:1 MANE Select	c.874C>T	p.Arg292Trp	missense	Exon 8 of 8	ENSP00000273064.6	Q92600-1
	CNOT9	ENST00000627282.2	TSL:2	c.970C>T	p.Arg324Trp	missense	Exon 9 of 9	ENSP00000486540.1	Q92600-2
	CNOT9	ENST00000934108.1		c.967C>T	p.Arg323Trp	missense	Exon 9 of 9	ENSP00000604167.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	CNOT9-associated neurodevelopmental disorder (1)
1	-	-	not provided (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.86	T
PhyloP100		0.75
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.25
Sift	Benign	0.032	D
Sift4G	Uncertain	0.023	D
Polyphen		0.99	D
Vest4		0.56
MutPred		0.34		Loss of disorder (P = 0.0022)
MVP		0.068
MPC		1.8
ClinPred		0.88	D
GERP RS		3.9
Varity_R		0.13
gMVP		0.52
Mutation Taster		=65/35	polymorphism

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: rs981210817; hg19: chr2-219458973; COSMIC: COSV55299652; COSMIC: COSV55299652;