2-218584667-G-T

Variant names:

• chr2-218584667-G-T
• NM_005444.3:c.376G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005444.3(CNOT9):​c.376G>T​(p.Val126Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNOT9 NM_005444.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.80

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT9	NM_005444.3	c.376G>T	p.Val126Phe	missense_variant	Exon 4 of 8	ENST00000273064.11	NP_005435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT9	ENST00000273064.11	c.376G>T	p.Val126Phe	missense_variant	Exon 4 of 8	1	NM_005444.3	ENSP00000273064.6
CNOT9	ENST00000295701.9	c.376G>T	p.Val126Phe	missense_variant	Exon 4 of 8	1		ENSP00000295701.5
CNOT9	ENST00000627282.2	c.376G>T	p.Val126Phe	missense_variant	Exon 4 of 9	2		ENSP00000486540.1
CNOT9	ENST00000432877.5	n.*268G>T		downstream_gene_variant		3		ENSP00000392394.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 27, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	.;T;T;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;.;D;D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Benign	-0.44	T
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.5	.;D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.011	.;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		0.58	.;P;P;.
Vest4		0.80
MutPred		0.58		Loss of catalytic residue at V126 (P = 0.0346);Loss of catalytic residue at V126 (P = 0.0346);Loss of catalytic residue at V126 (P = 0.0346);Loss of catalytic residue at V126 (P = 0.0346);
MVP		0.23
MPC		1.8
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.67
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.35		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-219449390;