Genetic Variant CNOT3:c.2163+424G>C (chr19-54154264-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001440655.1(CNOT3):c.*213G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 345,074 control chromosomes in the GnomAD database, including 56,313 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.59 ( 28317 hom., cov: 32)

Exomes 𝑓: 0.53 ( 27996 hom. )

Consequence

CNOT3
NM_001440655.1 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.35

Publications

9 publications found

Variant links:

Genes affected

CNOT3 (HGNC:7879): (CCR4-NOT transcription complex subunit 3) Involved in regulation of stem cell population maintenance. Part of CCR4-NOT complex. [provided by Alliance of Genome Resources, Apr 2022]

CNOT3 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
intellectual developmental disorder with speech delay, autism, and dysmorphic facies
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

CNOT3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440655.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CNOT3	NM_014516.4	MANE Select	c.2163+424G>C	intron	N/A	NP_055331.1	O75175
CNOT3	NM_001440655.1		c.*213G>C	3_prime_UTR	Exon 18 of 18	NP_001427584.1
CNOT3	NM_001440656.1		c.*213G>C	3_prime_UTR	Exon 18 of 18	NP_001427585.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CNOT3	ENST00000221232.11	TSL:1 MANE Select	c.2163+424G>C	intron	N/A	ENSP00000221232.5	O75175
CNOT3	ENST00000358389.7	TSL:1	c.2163+424G>C	intron	N/A	ENSP00000351159.4	O75175
CNOT3	ENST00000617930.2	TSL:2	c.*513G>C	3_prime_UTR	Exon 17 of 17	ENSP00000496602.1	B7Z6J7

Frequencies

GnomAD3 genomes

AF:

0.592

AC:

89971

AN:

151940

Hom.:

28280

Cov.:

show subpopulations

Gnomad AFR

AF:

0.797

Gnomad AMI

AF:

0.421

Gnomad AMR

AF:

0.622

Gnomad ASJ

AF:

0.608

Gnomad EAS

AF:

0.651

Gnomad SAS

AF:

0.650

Gnomad FIN

AF:

0.502

Gnomad MID

AF:

0.620

Gnomad NFE

AF:

0.468

Gnomad OTH

AF:

0.581

GnomAD4 exome

AF:

0.528

AC:

101866

AN:

193016

Hom.:

27996

Cov.:

AF XY:

0.539

AC XY:

56078

AN XY:

104024

show subpopulations

African (AFR)

AF:

0.802

AC:

4457

AN:

5554

American (AMR)

AF:

0.635

AC:

6945

AN:

10940

Ashkenazi Jewish (ASJ)

AF:

0.609

AC:

2830

AN:

4648

East Asian (EAS)

AF:

0.642

AC:

5696

AN:

8874

South Asian (SAS)

AF:

0.631

AC:

23592

AN:

37364

European-Finnish (FIN)

AF:

0.475

AC:

4067

AN:

8564

Middle Eastern (MID)

AF:

0.573

AC:

418

AN:

730

European-Non Finnish (NFE)

AF:

0.458

AC:

48837

AN:

106718

Other (OTH)

AF:

0.522

AC:

5024

AN:

9624

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

2080

4160

6239

8319

10399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

454

908

1362

1816

2270

<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:

0.592

AC:

90064

AN:

152058

Hom.:

28317

Cov.:

AF XY:

0.597

AC XY:

44342

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.798

AC:

33106

AN:

41508

American (AMR)

AF:

0.622

AC:

9500

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.608

AC:

2107

AN:

3468

East Asian (EAS)

AF:

0.650

AC:

3358

AN:

5164

South Asian (SAS)

AF:

0.650

AC:

3132

AN:

4822

European-Finnish (FIN)

AF:

0.502

AC:

5302

AN:

10554

Middle Eastern (MID)

AF:

0.612

AC:

180

AN:

294

European-Non Finnish (NFE)

AF:

0.468

AC:

31775

AN:

67962

Other (OTH)

AF:

0.578

AC:

1220

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1799

3599

5398

7198

8997

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

738

1476

2214

2952

3690

<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:

0.353

Hom.:

789

Bravo

AF:

0.610

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

4.6

(source)

PhyloP100

1.4

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over