chr5-180564741-C-G

Variant names:

• chr5-180564741-C-G
• rs373787258
• NM_001370472.1:c.557C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001370472.1(CNOT6):​c.557C>G​(p.Thr186Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,459,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. T186I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CNOT6 NM_001370472.1 missense, splice_region
• Scores: Splicing: ADA: 0.07021
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.16
• Publications: 0 publications found

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]

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=0.13055214).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370472.1. 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
	CNOT6	NM_001370472.1	MANE Select	c.557C>G	p.Thr186Ser	missense splice_region	Exon 6 of 12	NP_001357401.1	Q9ULM6
	CNOT6	NM_001370473.1		c.542C>G	p.Thr181Ser	missense splice_region	Exon 6 of 12	NP_001357402.1
	CNOT6	NM_001370474.1		c.272C>G	p.Thr91Ser	missense splice_region	Exon 5 of 11	NP_001357403.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT6	ENST00000261951.9	TSL:5 MANE Select	c.557C>G	p.Thr186Ser	missense splice_region	Exon 6 of 12	ENSP00000261951.4	Q9ULM6
	CNOT6	ENST00000393356.7	TSL:1	c.557C>G	p.Thr186Ser	missense splice_region	Exon 8 of 14	ENSP00000377024.1	Q9ULM6
	CNOT6	ENST00000618123.4	TSL:1	c.557C>G	p.Thr186Ser	missense splice_region	Exon 7 of 13	ENSP00000481893.1	Q9ULM6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459244 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726136

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

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109750

Other (OTH) AF: 0.00 AC: 0 AN: 60298

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	22
DANN	Benign	0.40
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.094
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.35	N
PhyloP100		7.2
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.068
Sift	Benign	0.81	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.22
MutPred		0.31		Gain of disorder (P = 0.0697)
MVP		0.40
MPC		0.54
ClinPred		0.67	D
GERP RS		5.3
Varity_R		0.081
gMVP		0.18
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.070
dbscSNV1_RF	Benign	0.35
SpliceAI score (max)		0.12		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: rs373787258; hg19: chr5-179991741;