16-58553833-C-T

Variant names:

• chr16-58553833-C-T
• rs11866002
• NM_016284.5:c.2919G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_016284.5(CNOT1):​c.2919G>A​(p.Gln973Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,608,122 control chromosomes in the GnomAD database, including 90,358 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12973 hom., cov: 32)
  • Exomes 𝑓: 0.31 (77385 hom.)
• Consequence: CNOT1 NM_016284.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.76

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 16-58553833-C-T is Benign according to our data. Variant chr16-58553833-C-T is described in ClinVar as [Benign]. Clinvar id is 1217378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.76 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT1	NM_016284.5	c.2919G>A	p.Gln973Gln	synonymous_variant	Exon 22 of 49	ENST00000317147.10	NP_057368.3
CNOT1	NM_001265612.2	c.2904G>A	p.Gln968Gln	synonymous_variant	Exon 22 of 49		NP_001252541.1
CNOT1	NM_206999.3	c.2919G>A	p.Gln973Gln	synonymous_variant	Exon 22 of 31		NP_996882.1
CNOT1	NR_049763.2	n.3177G>A		non_coding_transcript_exon_variant	Exon 22 of 50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT1	ENST00000317147.10	c.2919G>A	p.Gln973Gln	synonymous_variant	Exon 22 of 49	1	NM_016284.5	ENSP00000320949.5

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59294 AN: 151958 Hom.: 12950 Cov.: 32

Gnomad AFR AF: 0.589

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.384

GnomAD3 exomes AF: 0.352 AC: 87032 AN: 246930 Hom.: 17009 AF XY: 0.352 AC XY: 46952 AN XY: 133524

Gnomad AFR exome AF: 0.603

Gnomad AMR exome AF: 0.299

Gnomad ASJ exome AF: 0.373

Gnomad EAS exome AF: 0.565

Gnomad SAS exome AF: 0.428

Gnomad FIN exome AF: 0.256

Gnomad NFE exome AF: 0.297

Gnomad OTH exome AF: 0.329

GnomAD4 exome AF: 0.314 AC: 457838 AN: 1456046 Hom.: 77385 Cov.: 33 AF XY: 0.317 AC XY: 229886 AN XY: 724252

Gnomad4 AFR exome AF: 0.606

Gnomad4 AMR exome AF: 0.306

Gnomad4 ASJ exome AF: 0.376

Gnomad4 EAS exome AF: 0.608

Gnomad4 SAS exome AF: 0.427

Gnomad4 FIN exome AF: 0.257

Gnomad4 NFE exome AF: 0.286

Gnomad4 OTH exome AF: 0.341

GnomAD4 genome AF: 0.390 AC: 59361 AN: 152076 Hom.: 12973 Cov.: 32 AF XY: 0.391 AC XY: 29099 AN XY: 74348

Gnomad4 AFR AF: 0.590

Gnomad4 AMR AF: 0.322

Gnomad4 ASJ AF: 0.379

Gnomad4 EAS AF: 0.573

Gnomad4 SAS AF: 0.428

Gnomad4 FIN AF: 0.266

Gnomad4 NFE AF: 0.291

Gnomad4 OTH AF: 0.384

Alfa AF: 0.318 Hom.: 13441

Bravo AF: 0.403

Asia WGS AF: 0.485 AC: 1686 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Vissers-Bodmer syndrome Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Holoprosencephaly 12 with or without pancreatic agenesis Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CNOT1-related disorder Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	9.2
DANN	Benign	0.66

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

LitVar

Other links and lift over

dbSNP: rs11866002; hg19: chr16-58587737;