chr12-70335498-A-G

Position:

chr12-70335498-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_014515.7(CNOT2):c.710A>G(p.Asn237Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000442 in 1,607,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

CNOT2
NM_014515.7 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 4.88

Variant links:

Genes affected

CNOT2 (HGNC:7878): (CCR4-NOT transcription complex subunit 2) This gene encodes a subunit of the multi-component CCR4-NOT complex. The CCR4-NOT complex regulates mRNA synthesis and degradation and is also thought to be involved in mRNA splicing, transport and localization. The encoded protein interacts with histone deacetylases and functions as a repressor of polymerase II transcription. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Dec 2010]

CNOT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022284657).

BP6

Variant 12-70335498-A-G is Benign according to our data. Variant chr12-70335498-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1049790.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNOT2	NM_014515.7 link	c.710A>G	p.Asn237Ser	missense_variant	8/16	ENST00000229195.8	NP_055330.1	Q9NZN8-1A0A024RBD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNOT2	ENST00000229195.8 link	c.710A>G	p.Asn237Ser	missense_variant	8/16	1	NM_014515.7	ENSP00000229195.3		Q9NZN8-1

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000717

AC:

AN:

251208

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000220

AC:

AN:

1455228

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

724474

show subpopulations

Gnomad4 AFR exome

AF:

0.000782

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.04e-7

Gnomad4 OTH exome

AF:

0.0000832

GnomAD4 genome

AF:

0.000256

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000631

Hom.:

Bravo

AF:

0.000332

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The CNOT2 p.N237S variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs201309251) and in control databases in 22 of 282610 chromosomes at a frequency of 0.00007785, and was observed at the highest frequency in the African population in 21 of 24946 chromosomes (freq: 0.0008418) (Genome Aggregation Database March 6, 2019, v2.1.1). This frequency is greater than expected for the rare, autosomal dominant intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies condition associated with CNOT2 variants. The p.N237 residue is conserved in mammals however computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.054

.;T;T;T;.;.;T;T;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.88

D;D;.;D;D;D;D;D;.

M_CAP

Benign

0.021

MetaRNN

Benign

0.022

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.64

.;N;N;.;.;.;.;.;N

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.45

N;N;N;N;N;.;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.75

T;T;T;T;T;.;T;T;T

Sift4G

Benign

0.98

T;T;T;T;T;.;T;T;T

Polyphen

0.0

.;B;B;.;.;.;.;.;B

Vest4

0.13

MVP

0.64

MPC

0.80

ClinPred

0.085

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.050

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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