Variant 4-77742243-C-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_144571.3(CNOT6L):c.770G>T(p.Arg257Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,638 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: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CNOT6L
NM_144571.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.18

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:

Genome browser will be placed here

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=0.24661651).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNOT6L	NM_144571.3 link	c.770G>T	p.Arg257Leu	missense_variant	8/12	ENST00000504123.7	NP_653172.2	Q96LI5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNOT6L	ENST00000504123.7 link	c.770G>T	p.Arg257Leu	missense_variant	8/12	2	NM_144571.3	ENSP00000424896.1		Q96LI5-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152162

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247294

Hom.:

AF XY:

0.00000746

AC XY:

AN XY:

134128

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460638

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726536

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.00

Bravo

AF:

0.0000264

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 19, 2024

The c.770G>T (p.R257L) alteration is located in exon 8 (coding exon 8) of the CNOT6L gene. This alteration results from a G to T substitution at nucleotide position 770, causing the arginine (R) at amino acid position 257 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

0.17

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

.;T;.;.

Eigen

Benign

-0.24

Eigen_PC

Benign

0.044

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.98

.;D;D;D

M_CAP

Benign

0.052

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Uncertain

-0.067

MutationAssessor

Benign

-0.075

.;N;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.9

.;N;.;.

REVEL

Uncertain

0.37

Sift

Benign

0.39

.;T;.;.

Sift4G

Benign

0.72

.;T;.;.

Polyphen

0.0010

.;B;.;.

Vest4

0.57

MutPred

0.33

.;Gain of ubiquitination at K255 (P = 0.0582);.;.;

MVP

0.72

ClinPred

0.27

GERP RS

6.2

Varity_R

0.68

gMVP

0.88

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