Variant chr4-77726288-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_144571.3(CNOT6L):c.1334T>C(p.Met445Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000144 in 1,613,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

CNOT6L
NM_144571.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.19

Variant links:

Genes affected

CNOT6L (HGNC:18042): (CCR4-NOT transcription complex subunit 6 like) Predicted to enable poly(A)-specific ribonuclease activity. Involved in positive regulation of cell population proliferation and positive regulation of cytoplasmic mRNA processing body assembly. Located in cytosol and nucleus. Part of CCR4-NOT complex. [provided by Alliance of Genome Resources, Apr 2022]

CNOT6L links:

CNOT6L (HGNC:):

CNOT6L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01832077).

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNOT6L	NM_144571.3 linkuse as main transcript	c.1334T>C	p.Met445Thr	missense_variant	11/12	ENST00000504123.7	NP_653172.2	Q96LI5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNOT6L	ENST00000504123.7 linkuse as main transcript	c.1334T>C	p.Met445Thr	missense_variant	11/12	2	NM_144571.3	ENSP00000424896.1		Q96LI5-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000293

AC:

AN:

248790

Hom.:

AF XY:

0.000371

AC XY:

AN XY:

134946

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000836

Gnomad SAS exome

AF:

0.00157

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000151

AC:

220

AN:

1461538

Hom.:

Cov.:

AF XY:

0.000217

AC XY:

158

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.00153

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000612

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.000265

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2022

The c.1334T>C (p.M445T) alteration is located in exon 11 (coding exon 11) of the CNOT6L gene. This alteration results from a T to C substitution at nucleotide position 1334, causing the methionine (M) at amino acid position 445 to be replaced by a threonine (T). 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

0.065

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.59

DEOGEN2

Benign

0.14

.;T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.56

.;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.018

T;T;T

MetaSVM

Benign

-0.29

MutationAssessor

Benign

-1.4

.;N;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.69

.;N;.

REVEL

Uncertain

0.32

Sift

Benign

1.0

.;T;.

Sift4G

Benign

0.70

.;T;.

Polyphen

0.0

.;B;.

Vest4

0.34

MutPred

0.39

.;Gain of loop (P = 0.0312);.;

MVP

0.22

ClinPred

0.078

GERP RS

5.7

Varity_R

0.14

gMVP

0.58

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