5-180571349-G-A

Position:

• chr5-180571349-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001370472.1(CNOT6):​c.1378G>A​(p.Gly460Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CNOT6 NM_001370472.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.80

Genes affected

CNOT6 (HGNC:14099): (CCR4-NOT transcription complex subunit 6) This gene encodes the catalytic component of the CCR4-NOT core transcriptional regulation complex. The encoded protein has a 3'-5' RNase activity and prefers polyadenylated substrates. The CCR4-NOT complex plays a role in many cellular processes, including miRNA-mediated repression, mRNA degradation, and transcriptional regulation. [provided by RefSeq, Dec 2014]

CNOT6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNOT6	NM_001370472.1	c.1378G>A	p.Gly460Arg	missense_variant	11/12	ENST00000261951.9	NP_001357401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNOT6	ENST00000261951.9	c.1378G>A	p.Gly460Arg	missense_variant	11/12	5	NM_001370472.1	ENSP00000261951.4
CNOT6	ENST00000393356.7	c.1378G>A	p.Gly460Arg	missense_variant	13/14	1		ENSP00000377024.1
CNOT6	ENST00000618123.4	c.1378G>A	p.Gly460Arg	missense_variant	12/13	1		ENSP00000481893.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2022

The c.1378G>A (p.G460R) alteration is located in exon 11 (coding exon 10) of the CNOT6 gene. This alteration results from a G to A substitution at nucleotide position 1378, causing the glycine (G) at amino acid position 460 to be replaced by an arginine (R). 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	0.25
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;.;.
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.8	L;L;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.8	N;N;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.015	D;D;.
Sift4G	Benign	0.068	T;T;T
Polyphen		0.30	B;B;B
Vest4		0.66
MutPred		0.64		Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);
MVP		0.87
MPC		0.81
ClinPred		0.93	D
GERP RS		4.9
Varity_R		0.19
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-179998349;