Genetic Variant CNOT6:p.Lys118Ile (chr5-180553439-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001370472.1(CNOT6):c.353A>T(p.Lys118Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K118R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CNOT6
NM_001370472.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.48

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370472.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNOT6	NM_001370472.1	MANE Select	c.353A>T	p.Lys118Ile	missense	Exon 4 of 12	NP_001357401.1	Q9ULM6
CNOT6	NM_001370473.1		c.353A>T	p.Lys118Ile	missense	Exon 4 of 12	NP_001357402.1
CNOT6	NM_001370474.1		c.68A>T	p.Lys23Ile	missense	Exon 3 of 11	NP_001357403.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNOT6	ENST00000261951.9	TSL:5 MANE Select	c.353A>T	p.Lys118Ile	missense	Exon 4 of 12	ENSP00000261951.4	Q9ULM6
CNOT6	ENST00000393356.7	TSL:1	c.353A>T	p.Lys118Ile	missense	Exon 6 of 14	ENSP00000377024.1	Q9ULM6
CNOT6	ENST00000618123.4	TSL:1	c.353A>T	p.Lys118Ile	missense	Exon 5 of 13	ENSP00000481893.1	Q9ULM6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461672

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727152

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111890

Other (OTH)

AF:

0.00

AC:

AN:

60384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000286219), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.388

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.73

MetaSVM

Uncertain

0.19

MutationAssessor

Uncertain

2.4

PhyloP100

4.5

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.63

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0050

Polyphen

0.98

Vest4

0.67

MutPred

0.36

Loss of solvent accessibility (P = 0.0187)

MVP

0.92

MPC

1.1

ClinPred

0.99

GERP RS

5.3

Varity_R

0.45

gMVP

0.67

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over