chr2-218584614-C-T

Variant names:

• chr2-218584614-C-T
• NM_005444.3:c.323C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_005444.3(CNOT9):​c.323C>T​(p.Ser108Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNOT9 NM_005444.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.70
• Publications: 0 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 3 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).

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.323C>T	p.Ser108Leu	missense splice_region	Exon 4 of 8	NP_005435.1	Q92600-1
	CNOT9	NM_001271634.2		c.323C>T	p.Ser108Leu	missense splice_region	Exon 4 of 9	NP_001258563.1	Q92600-2
	CNOT9	NM_001271635.2		c.323C>T	p.Ser108Leu	missense splice_region	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.323C>T	p.Ser108Leu	missense splice_region	Exon 4 of 8	ENSP00000273064.6	Q92600-1
	CNOT9	ENST00000295701.9	TSL:1	c.323C>T	p.Ser108Leu	missense splice_region	Exon 4 of 8	ENSP00000295701.5	Q92600-3
	CNOT9	ENST00000627282.2	TSL:2	c.323C>T	p.Ser108Leu	missense splice_region	Exon 4 of 9	ENSP00000486540.1	Q92600-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.91	T
PhyloP100		7.7
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.18
Sift	Benign	0.25	T
Sift4G	Benign	0.32	T
Polyphen		0.73	P
Vest4		0.76
MutPred		0.43		Loss of disorder (P = 0.032)
MVP		0.043
MPC		1.5
ClinPred		0.97	D
GERP RS		4.3
Varity_R		0.46
gMVP		0.70
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr2-219449337;