12-70329504-C-T

Variant names:

• chr12-70329504-C-T
• rs956153106
• NM_014515.7:c.320C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_014515.7(CNOT2):​c.320C>T​(p.Pro107Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,459,206 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CNOT2 NM_014515.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.60
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2328035).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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.320C>T	p.Pro107Leu	missense	Exon 5 of 16	NP_055330.1	Q9NZN8-1
	CNOT2	NM_001199302.2		c.320C>T	p.Pro107Leu	missense	Exon 6 of 17	NP_001186231.1	Q9NZN8-1
	CNOT2	NM_001199303.2		c.320C>T	p.Pro107Leu	missense	Exon 5 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.320C>T	p.Pro107Leu	missense	Exon 5 of 16	ENSP00000229195.3	Q9NZN8-1
	CNOT2	ENST00000418359.7	TSL:1	c.320C>T	p.Pro107Leu	missense	Exon 6 of 17	ENSP00000412091.3	Q9NZN8-1
	CNOT2	ENST00000548159.5	TSL:1	c.293C>T	p.Pro98Leu	missense	Exon 6 of 17	ENSP00000449659.1	F8VV52

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459206 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726092

African (AFR) AF: 0.00 AC: 0 AN: 33350

American (AMR) AF: 0.00 AC: 0 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109890

Other (OTH) AF: 0.00 AC: 0 AN: 60254

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000471 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.091	T
Eigen	Benign	0.0099
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.16
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.042	D
Polyphen		0.18	B
Vest4		0.43
MutPred		0.20		Gain of catalytic residue at H109 (P = 0.0274)
MVP		0.22
MPC		1.0
ClinPred		0.88	D
GERP RS		5.5
Varity_R		0.19
gMVP		0.51
Mutation Taster		=71/29	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: rs956153106; hg19: chr12-70723284;