Variant 12-70329504-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS2

The NM_014515.7(CNOT2):c.320C>T(p.Pro107Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,459,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CNOT2
NM_014515.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.60

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2328035).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNOT2	NM_014515.7 link	c.320C>T	p.Pro107Leu	missense_variant	5/16	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.320C>T	p.Pro107Leu	missense_variant	5/16	1	NM_014515.7	ENSP00000229195.3		Q9NZN8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459206

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726092

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000471

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.320C>T (p.P107L) alteration is located in exon 5 (coding exon 4) of the CNOT2 gene. This alteration results from a C to T substitution at nucleotide position 320, causing the proline (P) at amino acid position 107 to be replaced by a leucine (L). 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

0.14

BayesDel_addAF

Benign

-0.046

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.091

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

Eigen

Benign

0.0099

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

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

M_CAP

Benign

0.017

MetaRNN

Benign

0.23

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

.;M;M;.;.;.;.;M;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.6

N;N;N;N;D;N;D;N;D;D

REVEL

Benign

0.16

Sift

Uncertain

0.0020

D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.042

D;T;T;T;D;T;D;T;T;D

Polyphen

0.18

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

Vest4

0.43, 0.43

MutPred

0.20

Gain of catalytic residue at H109 (P = 0.0274);Gain of catalytic residue at H109 (P = 0.0274);Gain of catalytic residue at H109 (P = 0.0274);Gain of catalytic residue at H109 (P = 0.0274);.;.;Gain of catalytic residue at H109 (P = 0.0274);Gain of catalytic residue at H109 (P = 0.0274);.;Gain of catalytic residue at H109 (P = 0.0274);

MVP

0.22

MPC

1.0

ClinPred

0.88

GERP RS

5.5

Varity_R

0.19

gMVP

0.51

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