16-58523468-C-G

Position:

chr16-58523468-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PP2PP3_ModerateBS1_SupportingBS2

The NM_016284.5(CNOT1):c.6819G>C(p.Gln2273His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

CNOT1
NM_016284.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.70

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 links:

SETD6 (HGNC:26116): (SET domain containing 6, protein lysine methyltransferase) This gene encodes a methyltransferase that adds a methyl group to the histone H2AZ, which is involved in nuclear receptor-dependent transcription. The protein also interacts with several endogenous proteins which are involved in nuclear hormone receptor signaling. A related pseudogene is located on chromosome 2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

SETD6 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CNOT1. . Gene score misZ 7.2546 (greater than the threshold 3.09). Trascript score misZ 9.1455 (greater than threshold 3.09). GenCC has associacion of gene with holoprosencephaly 12 with or without pancreatic agenesis, complex neurodevelopmental disorder, Vissers-Bodmer syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.895

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000039 (57/1461742) while in subpopulation NFE AF= 0.0000504 (56/1111906). AF 95% confidence interval is 0.0000398. There are 0 homozygotes in gnomad4_exome. There are 34 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CNOT1	NM_016284.5 linkuse as main transcript	c.6819G>C	p.Gln2273His	missense_variant	47/49	ENST00000317147.10	NP_057368.3
SETD6	NM_001160305.4 linkuse as main transcript	c.*4439C>G		3_prime_UTR_variant	8/8	ENST00000219315.9	NP_001153777.1
CNOT1	NM_001265612.2 linkuse as main transcript	c.6804G>C	p.Gln2268His	missense_variant	47/49		NP_001252541.1
CNOT1	NR_049763.2 linkuse as main transcript	n.7260G>C		non_coding_transcript_exon_variant	48/50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNOT1	ENST00000317147.10 linkuse as main transcript	c.6819G>C	p.Gln2273His	missense_variant	47/49	1	NM_016284.5	ENSP00000320949	P3	A5YKK6-1
SETD6	ENST00000219315.9 linkuse as main transcript	c.*4439C>G		3_prime_UTR_variant	8/8	1	NM_001160305.4	ENSP00000219315		Q8TBK2-1
	ENST00000622896.1 linkuse as main transcript	n.499C>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251414

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135890

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461742

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000504

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.6819G>C (p.Q2273H) alteration is located in exon 47 (coding exon 46) of the CNOT1 gene. This alteration results from a G to C substitution at nucleotide position 6819, causing the glutamine (Q) at amino acid position 2273 to be replaced by a histidine (H). 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

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.082

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.4

M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.96

D;P

Vest4

0.91

MutPred

0.77

Gain of disorder (P = 0.0665);.;

MVP

0.61

MPC

2.1

ClinPred

0.99

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.97

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