rs1161007517

Variant names:

• chr12-70329512-G-A
• rs1161007517
• NM_014515.7:c.328G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-70329512-G-A
• chr12-70329512-G-C
• chr12-70329512-G-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.328G>A​(p.Val110Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,611,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CNOT2 NM_014515.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.28
• Publications: 5 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=0.11139989).

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.328G>A	p.Val110Ile	missense	Exon 5 of 16	NP_055330.1	Q9NZN8-1
	CNOT2	NM_001199302.2		c.328G>A	p.Val110Ile	missense	Exon 6 of 17	NP_001186231.1	Q9NZN8-1
	CNOT2	NM_001199303.2		c.328G>A	p.Val110Ile	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.328G>A	p.Val110Ile	missense	Exon 5 of 16	ENSP00000229195.3	Q9NZN8-1
	CNOT2	ENST00000418359.7	TSL:1	c.328G>A	p.Val110Ile	missense	Exon 6 of 17	ENSP00000412091.3	Q9NZN8-1
	CNOT2	ENST00000548159.5	TSL:1	c.301G>A	p.Val101Ile	missense	Exon 6 of 17	ENSP00000449659.1	F8VV52

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151716 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: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459406 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726168

African (AFR) AF: 0.00 AC: 0 AN: 33352

American (AMR) AF: 0.00 AC: 0 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110054

Other (OTH) AF: 0.00 AC: 0 AN: 60280

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151716 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74068

African (AFR) AF: 0.00 AC: 0 AN: 41334

American (AMR) AF: 0.00 AC: 0 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67876

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000546

EpiControl AF: 0.00

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	0.070
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Benign	0.87
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.20	N
PhyloP100		4.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.071
Sift	Benign	0.36	T
Sift4G	Benign	0.72	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.18		Gain of catalytic residue at T114 (P = 0.0099)
MVP		0.22
MPC		0.82
ClinPred		0.67	D
GERP RS		5.5
Varity_R		0.078
gMVP		0.12
Mutation Taster		=88/12	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: rs1161007517; hg19: chr12-70723292; COSMIC: COSV57500539; COSMIC: COSV57500539;