Genetic Variant CNOT6:p.Ile285Val (chr5-180567223-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001370472.1(CNOT6):c.853A>G(p.Ile285Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000535 in 1,606,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

CNOT6
NM_001370472.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.26

Variant links:

Genes affected

CNOT6 (HGNC:14099): (CCR4-NOT transcription complex subunit 6) This gene encodes the catalytic component of the CCR4-NOT core transcriptional regulation complex. The encoded protein has a 3'-5' RNase activity and prefers polyadenylated substrates. The CCR4-NOT complex plays a role in many cellular processes, including miRNA-mediated repression, mRNA degradation, and transcriptional regulation. [provided by RefSeq, Dec 2014]

CNOT6 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11247951).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT6	NM_001370472.1 link	c.853A>G	p.Ile285Val	missense_variant	Exon 8 of 12	ENST00000261951.9	NP_001357401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNOT6	ENST00000261951.9 link	c.853A>G	p.Ile285Val	missense_variant	Exon 8 of 12	5	NM_001370472.1	ENSP00000261951.4	Q9ULM6
CNOT6	ENST00000393356.7 link	c.853A>G	p.Ile285Val	missense_variant	Exon 10 of 14	1		ENSP00000377024.1	Q9ULM6
CNOT6	ENST00000618123.4 link	c.853A>G	p.Ile285Val	missense_variant	Exon 9 of 13	1		ENSP00000481893.1	Q9ULM6
CNOT6	ENST00000504343.1 link	c.565A>G	p.Ile189Val	missense_variant	Exon 5 of 6	3		ENSP00000422087.1	D6R9H6

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000703

AC:

AN:

241800

Hom.:

AF XY:

0.0000383

AC XY:

AN XY:

130650

show subpopulations

Gnomad AFR exome

AF:

0.000685

Gnomad AMR exome

AF:

0.0000947

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000270

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000385

AC:

AN:

1453706

Hom.:

Cov.:

AF XY:

0.0000318

AC XY:

AN XY:

723034

show subpopulations

Gnomad4 AFR exome

AF:

0.000640

Gnomad4 AMR exome

AF:

0.000190

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000237

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000197

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.000601

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000630

Hom.:

Bravo

AF:

0.000212

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.853A>G (p.I285V) alteration is located in exon 8 (coding exon 7) of the CNOT6 gene. This alteration results from a A to G substitution at nucleotide position 853, causing the isoleucine (I) at amino acid position 285 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

T;T;T;T

Eigen

Benign

-0.044

Eigen_PC

Benign

0.054

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

D;.;.;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.8

L;L;L;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.75

N;N;.;N

REVEL

Uncertain

0.41

Sift

Benign

0.11

T;T;.;T

Sift4G

Benign

0.095

T;T;T;T

Polyphen

0.060

B;B;B;B

Vest4

0.30

MVP

0.47

MPC

0.52

ClinPred

0.028

GERP RS

3.9

Varity_R

0.073

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over