chr12-70329453-G-A

Variant names:

• chr12-70329453-G-A
• rs771989980
• NM_014515.7:c.269G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014515.7(CNOT2):​c.269G>A​(p.Ser90Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000639 in 1,409,412 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: CNOT2 NM_014515.7 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.25
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12842554).
• BS2: High AC in GnomAdExome4 at 8 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.269G>A	p.Ser90Asn	missense	Exon 5 of 16	NP_055330.1	Q9NZN8-1
	CNOT2	NM_001199302.2		c.269G>A	p.Ser90Asn	missense	Exon 6 of 17	NP_001186231.1	Q9NZN8-1
	CNOT2	NM_001199303.2		c.269G>A	p.Ser90Asn	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.269G>A	p.Ser90Asn	missense	Exon 5 of 16	ENSP00000229195.3	Q9NZN8-1
	CNOT2	ENST00000418359.7	TSL:1	c.269G>A	p.Ser90Asn	missense	Exon 6 of 17	ENSP00000412091.3	Q9NZN8-1
	CNOT2	ENST00000548159.5	TSL:1	c.242G>A	p.Ser81Asn	missense	Exon 6 of 17	ENSP00000449659.1	F8VV52

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150584 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: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250746 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000636 AC: 8 AN: 1258828 Hom.: 0 Cov.: 29 AF XY: 0.00000788 AC XY: 5 AN XY: 634328

African (AFR) AF: 0.00 AC: 0 AN: 29404

American (AMR) AF: 0.0000902 AC: 4 AN: 44328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24814

East Asian (EAS) AF: 0.00 AC: 0 AN: 38736

South Asian (SAS) AF: 0.00 AC: 0 AN: 82170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5300

European-Non Finnish (NFE) AF: 0.00000431 AC: 4 AN: 927070

Other (OTH) AF: 0.00 AC: 0 AN: 53722

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150584 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73442

African (AFR) AF: 0.00 AC: 0 AN: 40910

American (AMR) AF: 0.00 AC: 0 AN: 15044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5070

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67672

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	CNOT2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.089
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.2
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.085
Sift	Benign	0.036	D
Sift4G	Benign	0.51	T
Polyphen		0.18	B
Vest4		0.20
MutPred		0.13		Gain of catalytic residue at M89 (P = 0.0213)
MVP		0.50
MPC		0.99
ClinPred		0.16	T
GERP RS		5.5
Varity_R		0.13
gMVP		0.33
Mutation Taster		=90/10	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: rs771989980; hg19: chr12-70723233;