NM_001190850.2:c.2086C>A

Variant names:

• chr7-135362941-G-T
• rs201606362
• NM_001190850.2:c.2086C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001190850.2(CNOT4):​c.2086C>A​(p.Pro696Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,612,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CNOT4 NM_001190850.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.80
• Publications: 4 publications found

Genes affected

CNOT4 (HGNC:7880): (CCR4-NOT transcription complex subunit 4) The protein encoded by this gene is a subunit of the CCR4-NOT complex, a global transcriptional regulator. The encoded protein interacts with CNOT1 and has E3 ubiquitin ligase activity. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3537956).
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001190850.2. 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
	CNOT4	NM_001190850.2	MANE Select	c.2086C>A	p.Pro696Thr	missense	Exon 12 of 12	NP_001177779.1	O95628-10
	CNOT4	NM_001393370.1		c.2086C>A	p.Pro696Thr	missense	Exon 13 of 13	NP_001380299.1	O95628-10
	CNOT4	NM_001190849.2		c.2077C>A	p.Pro693Thr	missense	Exon 12 of 12	NP_001177778.1	O95628-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT4	ENST00000541284.6	TSL:5 MANE Select	c.2086C>A	p.Pro696Thr	missense	Exon 12 of 12	ENSP00000445508.1	O95628-10
	CNOT4	ENST00000423368.6	TSL:1	c.1873C>A	p.Pro625Thr	missense	Exon 11 of 11	ENSP00000406777.2	O95628-4
	CNOT4	ENST00000361528.8	TSL:1	c.1864C>A	p.Pro622Thr	missense	Exon 11 of 11	ENSP00000354673.4	O95628-8

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151518 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

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249180 AF XY: 0.00000740

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461206 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 726934

African (AFR) AF: 0.0000299 AC: 1 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111468

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151518 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73942

African (AFR) AF: 0.00 AC: 0 AN: 41172

American (AMR) AF: 0.00 AC: 0 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10528

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67932

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.58	T
PhyloP100		7.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.59
MutPred		0.19		Gain of phosphorylation at P696 (P = 0.0039)
MVP		0.49
MPC		0.82
ClinPred		0.66	D
GERP RS		5.9
gMVP		0.57
Mutation Taster		=58/42	polymorphism

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: rs201606362; hg19: chr7-135047693;