12-70330306-C-T

Position:

• chr12-70330306-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014515.7(CNOT2):​c.406C>T​(p.Pro136Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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: 2.27

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0980615).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNOT2	NM_014515.7	c.406C>T	p.Pro136Ser	missense_variant	6/16	ENST00000229195.8	NP_055330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNOT2	ENST00000229195.8	c.406C>T	p.Pro136Ser	missense_variant	6/16	1	NM_014515.7	ENSP00000229195.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Benign	0.040	.;T;T;.;T;T;T;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.012
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D;D;.;D;D;D;.;D;D
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.098	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.44	.;N;N;.;.;.;N;.;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.26	N;N;N;D;N;D;N;D;D
REVEL	Benign	0.10
Sift	Benign	0.53	T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T
Polyphen		0.0010	.;B;B;.;.;.;B;.;.
Vest4		0.084
MutPred		0.23		Gain of catalytic residue at L132 (P = 0.0032);Gain of catalytic residue at L132 (P = 0.0032);Gain of catalytic residue at L132 (P = 0.0032);.;.;Gain of catalytic residue at L132 (P = 0.0032);Gain of catalytic residue at L132 (P = 0.0032);.;Gain of catalytic residue at L132 (P = 0.0032);
MVP		0.17
MPC		1.0
ClinPred		0.34	T
GERP RS		5.5
Varity_R		0.049
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-70724086;