rs11644694

Variant names:

• chr16-58523438-G-A
• rs11644694
• NM_016284.5:c.6849C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_016284.5(CNOT1):​c.6849C>T​(p.Tyr2283Tyr) variant causes a synonymous change. The variant allele was found at a frequency of 0.0396 in 1,613,818 control chromosomes in the GnomAD database, including 1,456 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (84 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1372 hom.)
• Consequence: CNOT1 NM_016284.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.75
• Publications: 10 publications found

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]

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 Gene-Disease associations (from GenCC):

• colorectal cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine

ENSG00000276259 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.132).
• BP6: Variant 16-58523438-G-A is Benign according to our data. Variant chr16-58523438-G-A is described in ClinVar as Benign. ClinVar VariationId is 1569231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0296 (4510/152286) while in subpopulation NFE AF = 0.0482 (3276/68004). AF 95% confidence interval is 0.0468. There are 84 homozygotes in GnomAd4. There are 2086 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4510 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT1	NM_016284.5	c.6849C>T	p.Tyr2283Tyr	synonymous_variant	Exon 47 of 49	ENST00000317147.10	NP_057368.3
SETD6	NM_001160305.4	c.*4409G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000219315.9	NP_001153777.1
CNOT1	NM_001265612.2	c.6834C>T	p.Tyr2278Tyr	synonymous_variant	Exon 47 of 49		NP_001252541.1
CNOT1	NR_049763.2	n.7290C>T		non_coding_transcript_exon_variant	Exon 48 of 50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT1	ENST00000317147.10	c.6849C>T	p.Tyr2283Tyr	synonymous_variant	Exon 47 of 49	1	NM_016284.5	ENSP00000320949.5
SETD6	ENST00000219315.9	c.*4409G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_001160305.4	ENSP00000219315.5

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4511 AN: 152168 Hom.: 84 Cov.: 32

Gnomad AFR AF: 0.00835

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0299

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0482

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.0285 AC: 7154 AN: 251434 AF XY: 0.0285

Gnomad AFR exome AF: 0.00751

Gnomad AMR exome AF: 0.0203

Gnomad ASJ exome AF: 0.0266

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0200

Gnomad NFE exome AF: 0.0456

Gnomad OTH exome AF: 0.0308

GnomAD4 exome AF: 0.0406 AC: 59342 AN: 1461532 Hom.: 1372 Cov.: 31 AF XY: 0.0394 AC XY: 28676 AN XY: 727064

African (AFR) AF: 0.00624 AC: 209 AN: 33472

American (AMR) AF: 0.0227 AC: 1014 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 720 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00814 AC: 702 AN: 86248

European-Finnish (FIN) AF: 0.0214 AC: 1143 AN: 53410

Middle Eastern (MID) AF: 0.0198 AC: 114 AN: 5768

European-Non Finnish (NFE) AF: 0.0479 AC: 53232 AN: 1111710

Other (OTH) AF: 0.0366 AC: 2207 AN: 60378

GnomAD4 genome AF: 0.0296 AC: 4510 AN: 152286 Hom.: 84 Cov.: 32 AF XY: 0.0280 AC XY: 2086 AN XY: 74468

African (AFR) AF: 0.00832 AC: 346 AN: 41568

American (AMR) AF: 0.0298 AC: 456 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 98 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00932 AC: 45 AN: 4828

European-Finnish (FIN) AF: 0.0170 AC: 181 AN: 10620

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0482 AC: 3276 AN: 68004

Other (OTH) AF: 0.0298 AC: 63 AN: 2112

Alfa AF: 0.0405 Hom.: 433

Bravo AF: 0.0297

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0477

EpiControl AF: 0.0493

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

CNOT1-related disorder Benign:1

Dec 11, 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	-0.44
CADD	Benign	18
DANN	Benign	0.85
PhyloP100		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11644694; hg19: chr16-58557342;