NM_014515.7:c.320C>T

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT2	NM_014515.7	c.320C>T	p.Pro107Leu	missense_variant	Exon 5 of 16	ENST00000229195.8	NP_055330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT2	ENST00000229195.8	c.320C>T	p.Pro107Leu	missense_variant	Exon 5 of 16	1	NM_014515.7	ENSP00000229195.3

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000471 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.320C>T (p.P107L) alteration is located in exon 5 (coding exon 4) of the CNOT2 gene. This alteration results from a C to T substitution at nucleotide position 320, causing the proline (P) at amino acid position 107 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T;.;.;T;T;T;.;T
Eigen	Benign	0.0099
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D;D;D;.;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	.;M;M;.;.;.;.;M;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.6	N;N;N;N;D;N;D;N;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.042	D;T;T;T;D;T;D;T;T;D
Polyphen		0.18	.;B;B;.;.;.;.;B;.;.
Vest4		0.43, 0.43
MutPred		0.20		Gain of catalytic residue at H109 (P = 0.0274);Gain of catalytic residue at H109 (P = 0.0274);Gain of catalytic residue at H109 (P = 0.0274);Gain of catalytic residue at H109 (P = 0.0274);.;.;Gain of catalytic residue at H109 (P = 0.0274);Gain of catalytic residue at H109 (P = 0.0274);.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs956153106; hg19: chr12-70723284;