ENST00000441024.6:c.4629dupT

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PVS1_ModerateBP6_Very_StrongBS2

The ENST00000441024.6(CNOT1):c.4629dupT(p.Leu1544SerfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,089,636 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 1 hom., cov: 21)

Exomes 𝑓: 0.16 ( 0 hom. )

Consequence

CNOT1
ENST00000441024.6 frameshift

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0160

Publications

13 publications found

Variant links:

Genes affected

CNOT1 (HGNC:7877): (CCR4-NOT transcription complex subunit 1) Enables armadillo repeat domain binding activity; molecular adaptor activity; and nuclear receptor binding activity. Contributes to poly(A)-specific ribonuclease activity. Involved in several processes, including negative regulation of signal transduction; positive regulation of cytoplasmic mRNA processing body assembly; and regulation of gene expression. Located in P-body and cytosol. Part of CCR4-NOT complex. Implicated in holoprosencephaly. [provided by Alliance of Genome Resources, Apr 2022]

CNOT1 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
holoprosencephaly 12 with or without pancreatic agenesis
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
Vissers-Bodmer syndrome
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

CNOT1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript ENST00000441024.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0058 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

BP6

Variant 16-58543411-G-GA is Benign according to our data. Variant chr16-58543411-G-GA is described in ClinVar as Benign. ClinVar VariationId is 587551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 410 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000441024.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNOT1	NM_016284.5	MANE Select	c.4434+195dupT		intron	N/A	NP_057368.3
CNOT1	NM_206999.3		c.4629dupT	p.Leu1544SerfsTer22	frameshift	Exon 31 of 31	NP_996882.1	A5YKK6-4
CNOT1	NM_001265612.2		c.4419+195dupT		intron	N/A	NP_001252541.1	A5YKK6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNOT1	ENST00000441024.6	TSL:1	c.4629dupT	p.Leu1544SerfsTer22	frameshift	Exon 31 of 31	ENSP00000413113.2	A5YKK6-4
CNOT1	ENST00000317147.10	TSL:1 MANE Select	c.4434+195dupT		intron	N/A	ENSP00000320949.5	A5YKK6-1
CNOT1	ENST00000569240.5	TSL:1	c.4419+195dupT		intron	N/A	ENSP00000455635.1	A5YKK6-2

Frequencies

GnomAD3 genomes

AF:

0.00312

AC:

405

AN:

129714

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00542

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00358

Gnomad ASJ

AF:

0.00126

Gnomad EAS

AF:

0.00193

Gnomad SAS

AF:

0.00139

Gnomad FIN

AF:

0.00177

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00214

Gnomad OTH

AF:

0.00691

GnomAD2 exomes

AF:

0.148

AC:

10061

AN:

68028

AF XY:

0.150

show subpopulations

Gnomad AFR exome

AF:

0.233

Gnomad AMR exome

AF:

0.122

Gnomad ASJ exome

AF:

0.158

Gnomad EAS exome

AF:

0.124

Gnomad FIN exome

AF:

0.117

Gnomad NFE exome

AF:

0.159

Gnomad OTH exome

AF:

0.162

GnomAD4 exome

AF:

0.159

AC:

152156

AN:

959856

Hom.:

Cov.:

AF XY:

0.159

AC XY:

74431

AN XY:

469534

show subpopulations

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

African (AFR)

AF:

0.228

AC:

4350

AN:

19094

American (AMR)

AF:

0.112

AC:

1977

AN:

17702

Ashkenazi Jewish (ASJ)

AF:

0.164

AC:

2541

AN:

15478

East Asian (EAS)

AF:

0.119

AC:

3294

AN:

27598

South Asian (SAS)

AF:

0.142

AC:

7521

AN:

53026

European-Finnish (FIN)

AF:

0.128

AC:

4599

AN:

35874

Middle Eastern (MID)

AF:

0.129

AC:

514

AN:

3980

European-Non Finnish (NFE)

AF:

0.162

AC:

121064

AN:

747128

Other (OTH)

AF:

0.157

AC:

6296

AN:

39976

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.259

Heterozygous variant carriers

18610

37220

55830

74440

93050

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

4648

9296

13944

18592

23240

<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

AF:

0.00316

AC:

410

AN:

129780

Hom.:

Cov.:

AF XY:

0.00350

AC XY:

219

AN XY:

62528

show subpopulations

African (AFR)

AF:

0.00552

AC:

189

AN:

34242

American (AMR)

AF:

0.00357

AC:

AN:

13432

Ashkenazi Jewish (ASJ)

AF:

0.00126

AC:

AN:

3182

East Asian (EAS)

AF:

0.00194

AC:

AN:

4632

South Asian (SAS)

AF:

0.00116

AC:

AN:

4294

European-Finnish (FIN)

AF:

0.00177

AC:

AN:

7350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00214

AC:

128

AN:

59908

Other (OTH)

AF:

0.00797

AC:

AN:

1756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

176

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.016

Mutation Taster

=123/77

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over