16-58520968-C-G

Position:

chr16-58520968-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_016284.5(CNOT1):c.7121G>C(p.Gly2374Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

CNOT1
NM_016284.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.84

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.2118389).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CNOT1	NM_016284.5 linkuse as main transcript	c.7121G>C	p.Gly2374Ala	missense_variant	49/49	ENST00000317147.10	NP_057368.3
SETD6	NM_001160305.4 linkuse as main transcript	c.*1939C>G		3_prime_UTR_variant	8/8	ENST00000219315.9	NP_001153777.1
CNOT1	NM_001265612.2 linkuse as main transcript	c.7106G>C	p.Gly2369Ala	missense_variant	49/49		NP_001252541.1
CNOT1	NR_049763.2 linkuse as main transcript	n.7562G>C		non_coding_transcript_exon_variant	50/50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNOT1	ENST00000317147.10 linkuse as main transcript	c.7121G>C	p.Gly2374Ala	missense_variant	49/49	1	NM_016284.5	ENSP00000320949	P3	A5YKK6-1
SETD6	ENST00000219315.9 linkuse as main transcript	c.*1939C>G		3_prime_UTR_variant	8/8	1	NM_001160305.4	ENSP00000219315		Q8TBK2-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 18, 2023

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.048

T;.

Eigen

Benign

0.0092

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.0074

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.63

N;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.59

N;N

REVEL

Benign

0.091

Sift

Benign

0.12

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.14

B;B

Vest4

0.49

MutPred

0.58

Gain of helix (P = 0.0496);.;

MVP

0.20

MPC

1.2

ClinPred

0.63

GERP RS

5.6

Varity_R

0.24

gMVP

0.27

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