chr16-58521252-T-C

Variant names:

• chr16-58521252-T-C
• rs2039357202
• NM_016284.5:c.6983A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016284.5(CNOT1):​c.6983A>G​(p.Glu2328Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.82
• Publications: 0 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016284.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT1	NM_016284.5	MANE Select	c.6983A>G	p.Glu2328Gly	missense	Exon 48 of 49	NP_057368.3
	SETD6	NM_001160305.4	MANE Select	c.*2223T>C		3_prime_UTR	Exon 8 of 8	NP_001153777.1	Q8TBK2-1
	CNOT1	NM_001265612.2		c.6968A>G	p.Glu2323Gly	missense	Exon 48 of 49	NP_001252541.1	A5YKK6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT1	ENST00000317147.10	TSL:1 MANE Select	c.6983A>G	p.Glu2328Gly	missense	Exon 48 of 49	ENSP00000320949.5	A5YKK6-1
	CNOT1	ENST00000569240.5	TSL:1	c.6968A>G	p.Glu2323Gly	missense	Exon 48 of 49	ENSP00000455635.1	A5YKK6-2
	SETD6	ENST00000219315.9	TSL:1 MANE Select	c.*2223T>C		3_prime_UTR	Exon 8 of 8	ENSP00000219315.5	Q8TBK2-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74330

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.82		Loss of stability (P = 0.0441)
MVP		0.86
MPC		2.5
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.78
gMVP		0.91

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

Other links and lift over

dbSNP: rs2039357202; hg19: chr16-58555156;