chr12-70335494-C-G

Position:

• chr12-70335494-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014515.7(CNOT2):​c.706C>G​(p.Arg236Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNOT2 NM_014515.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18

Genes affected

CNOT2 (HGNC:7878): (CCR4-NOT transcription complex subunit 2) This gene encodes a subunit of the multi-component CCR4-NOT complex. The CCR4-NOT complex regulates mRNA synthesis and degradation and is also thought to be involved in mRNA splicing, transport and localization. The encoded protein interacts with histone deacetylases and functions as a repressor of polymerase II transcription. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNOT2	NM_014515.7	c.706C>G	p.Arg236Gly	missense_variant	8/16	ENST00000229195.8	NP_055330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNOT2	ENST00000229195.8	c.706C>G	p.Arg236Gly	missense_variant	8/16	1	NM_014515.7	ENSP00000229195.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2024

The c.706C>G (p.R236G) alteration is located in exon 8 (coding exon 7) of the CNOT2 gene. This alteration results from a C to G substitution at nucleotide position 706, causing the arginine (R) at amino acid position 236 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	.;T;T;T;.;.;T;T;T
Eigen	Benign	0.062
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D;.;D;D;D;D;D;.
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.0	.;M;M;.;.;.;.;.;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.9	N;N;N;N;N;.;N;N;N
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;D;D;D;D;.;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;.;D;D;D
Polyphen		0.021	.;B;B;.;.;.;.;.;B
Vest4		0.82
MutPred		0.39		Gain of relative solvent accessibility (P = 0.0098);Gain of relative solvent accessibility (P = 0.0098);Gain of relative solvent accessibility (P = 0.0098);.;.;.;.;.;Gain of relative solvent accessibility (P = 0.0098);
MVP		0.95
MPC		1.8
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.41
gMVP		0.95

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: rs1880558085; hg19: chr12-70729274;