rs1057519955

Variant names:

• chr2-218584682-C-T
• rs1057519955
• NM_005444.3:c.391C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_005444.3(CNOT9):​c.391C>T​(p.Pro131Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P131L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNOT9 NM_005444.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.75
• Publications: 3 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT9	NM_005444.3	MANE Select	c.391C>T	p.Pro131Ser	missense	Exon 4 of 8	NP_005435.1
	CNOT9	NM_001271634.2		c.391C>T	p.Pro131Ser	missense	Exon 4 of 9	NP_001258563.1
	CNOT9	NM_001271635.2		c.391C>T	p.Pro131Ser	missense	Exon 4 of 8	NP_001258564.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT9	ENST00000273064.11	TSL:1 MANE Select	c.391C>T	p.Pro131Ser	missense	Exon 4 of 8	ENSP00000273064.6
	CNOT9	ENST00000295701.9	TSL:1	c.391C>T	p.Pro131Ser	missense	Exon 4 of 8	ENSP00000295701.5
	CNOT9	ENST00000627282.2	TSL:2	c.391C>T	p.Pro131Ser	missense	Exon 4 of 9	ENSP00000486540.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.87	T
PhyloP100		7.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.30
Sift	Benign	0.16	T
Sift4G	Benign	0.17	T
Polyphen		0.39	B
Vest4		0.70
MutPred		0.51		Gain of sheet (P = 0.0477)
MVP		0.37
MPC		1.4
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.63
gMVP		0.60
Mutation Taster		=15/85	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: rs1057519955; hg19: chr2-219449405; COSMIC: COSV55299045; COSMIC: COSV55299045;