2-218594250-C-T

Position:

• chr2-218594250-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1 PM2 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

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a chain CCR4-NOT transcription complex subunit 9 (size 298) in uniprot entity CNOT9_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_005444.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-218594250-C-T is Pathogenic according to our data. Variant chr2-218594250-C-T is described in ClinVar as [Pathogenic]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNOT9	NM_005444.3	c.874C>T	p.Arg292Trp	missense_variant	8/8	ENST00000273064.11
CNOT9	NM_001271634.2	c.970C>T	p.Arg324Trp	missense_variant	9/9
CNOT9	XM_047446271.1	c.715C>T	p.Arg239Trp	missense_variant	7/7
CNOT9	NR_073390.2	n.880C>T		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNOT9	ENST00000273064.11	c.874C>T	p.Arg292Trp	missense_variant	8/8	1	NM_005444.3	P1
CNOT9	ENST00000627282.2	c.970C>T	p.Arg324Trp	missense_variant	9/9	2
CNOT9	ENST00000418808.1	c.*75C>T		3_prime_UTR_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

research

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Sep 27, 2022

PS2_VSTR, PM2_SUP, PP2 -

CNOT9-associated neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Sep 28, 2022

PS2_VSTR, PM2_SUP, PP2 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 22, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D;.;D
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.6	.;N;N
REVEL	Benign	0.25
Sift	Benign	0.032	.;D;D
Sift4G	Uncertain	0.023	D;D;D
Polyphen		0.99	.;D;D
Vest4		0.56
MutPred		0.34		.;Loss of disorder (P = 0.0022);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

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