12-70330300-A-G

Variant names:

• chr12-70330300-A-G
• rs763477147
• NM_014515.7:c.400A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014515.7(CNOT2):​c.400A>G​(p.Met134Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000107 in 1,590,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CNOT2 NM_014515.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.88

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24771458).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT2	NM_014515.7	c.400A>G	p.Met134Val	missense_variant	Exon 6 of 16	ENST00000229195.8	NP_055330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT2	ENST00000229195.8	c.400A>G	p.Met134Val	missense_variant	Exon 6 of 16	1	NM_014515.7	ENSP00000229195.3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151952 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000123 AC: 3 AN: 244056 Hom.: 0 AF XY: 0.0000152 AC XY: 2 AN XY: 131904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000680

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1439038 Hom.: 0 Cov.: 27 AF XY: 0.0000153 AC XY: 11 AN XY: 716824

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.0000231

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000473

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000639

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151952 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74220

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.070	.;T;T;.;T;T;T;.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;.;D;D;D;.;D;D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	.;L;L;.;.;.;L;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.71	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.16	T;D;D;T;D;T;D;T;T
Sift4G	Benign	0.57	T;T;T;T;T;T;T;D;T
Polyphen		0.92	.;P;P;.;.;.;P;.;.
Vest4		0.60
MutPred		0.27		Gain of catalytic residue at P133 (P = 0.0057);Gain of catalytic residue at P133 (P = 0.0057);Gain of catalytic residue at P133 (P = 0.0057);.;.;Gain of catalytic residue at P133 (P = 0.0057);Gain of catalytic residue at P133 (P = 0.0057);.;Gain of catalytic residue at P133 (P = 0.0057);
MVP		0.55
MPC		1.0
ClinPred		0.26	T
GERP RS		5.5
Varity_R		0.41
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs763477147; hg19: chr12-70724080;