12-70330306-C-T

Variant names:

• chr12-70330306-C-T
• NM_014515.7:c.406C>T

Variant summary

Our verdict is Uncertain significance. The variant received 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. 15/22 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
• Publications: 0 publications found

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]

CNOT2 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014515.7. 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
	CNOT2	NM_014515.7	MANE Select	c.406C>T	p.Pro136Ser	missense	Exon 6 of 16	NP_055330.1	Q9NZN8-1
	CNOT2	NM_001199302.2		c.406C>T	p.Pro136Ser	missense	Exon 7 of 17	NP_001186231.1	Q9NZN8-1
	CNOT2	NM_001199303.2		c.406C>T	p.Pro136Ser	missense	Exon 6 of 16	NP_001186232.1	Q9NZN8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT2	ENST00000229195.8	TSL:1 MANE Select	c.406C>T	p.Pro136Ser	missense	Exon 6 of 16	ENSP00000229195.3	Q9NZN8-1
	CNOT2	ENST00000418359.7	TSL:1	c.406C>T	p.Pro136Ser	missense	Exon 7 of 17	ENSP00000412091.3	Q9NZN8-1
	CNOT2	ENST00000548159.5	TSL:1	c.379C>T	p.Pro127Ser	missense	Exon 7 of 17	ENSP00000449659.1	F8VV52

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.23
Eigen_PC	Benign	0.012
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.44	N
PhyloP100		2.3
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.10
Sift	Benign	0.53	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.084
MutPred		0.23		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
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

hg19: chr12-70724086;