12-70329453-G-C

Variant names:

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

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.269G>C​(p.Ser90Thr) 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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S90N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CNOT2 NM_014515.7 missense
• Clinical Significance: Not reported in ClinVar
• 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: 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=0.17389989).

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>C	p.Ser90Thr	missense	Exon 5 of 16	NP_055330.1	Q9NZN8-1
	CNOT2	NM_001199302.2		c.269G>C	p.Ser90Thr	missense	Exon 6 of 17	NP_001186231.1	Q9NZN8-1
	CNOT2	NM_001199303.2		c.269G>C	p.Ser90Thr	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>C	p.Ser90Thr	missense	Exon 5 of 16	ENSP00000229195.3	Q9NZN8-1
	CNOT2	ENST00000418359.7	TSL:1	c.269G>C	p.Ser90Thr	missense	Exon 6 of 17	ENSP00000412091.3	Q9NZN8-1
	CNOT2	ENST00000548159.5	TSL:1	c.242G>C	p.Ser81Thr	missense	Exon 6 of 17	ENSP00000449659.1	F8VV52

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00371 AC: 4609 AN: 1242656 Hom.: 0 Cov.: 29 AF XY: 0.00338 AC XY: 2118 AN XY: 626932

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00334 AC: 97 AN: 29006

American (AMR) AF: 0.000135 AC: 6 AN: 44298

Ashkenazi Jewish (ASJ) AF: 0.00125 AC: 31 AN: 24724

East Asian (EAS) AF: 0.000621 AC: 24 AN: 38672

South Asian (SAS) AF: 0.00123 AC: 101 AN: 81804

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53272

Middle Eastern (MID) AF: 0.00114 AC: 6 AN: 5276

European-Non Finnish (NFE) AF: 0.00460 AC: 4194 AN: 912474

Other (OTH) AF: 0.00280 AC: 149 AN: 53130

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.087
Sift	Benign	0.063	T
Sift4G	Benign	0.60	T
Polyphen		0.18	B
Vest4		0.46
MutPred		0.12		Gain of catalytic residue at M89 (P = 0.0256)
MVP		0.45
MPC		0.97
ClinPred		0.52	D
GERP RS		5.5
Varity_R		0.13
gMVP		0.34
Mutation Taster		=89/11	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;