chr4-77774704-C-A

Variant names:

• chr4-77774704-C-A
• rs766542626
• NM_144571.3:c.140G>T

Variant summary

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

The NM_144571.3(CNOT6L):​c.140G>T​(p.Ser47Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000697 in 1,434,746 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S47N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CNOT6L NM_144571.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.06
• Publications: 0 publications found

Genes affected

CNOT6L (HGNC:18042): (CCR4-NOT transcription complex subunit 6 like) Predicted to enable poly(A)-specific ribonuclease activity. Involved in positive regulation of cell population proliferation and positive regulation of cytoplasmic mRNA processing body assembly. Located in cytosol and nucleus. Part of CCR4-NOT complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144571.3. 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
	CNOT6L	NM_144571.3	MANE Select	c.140G>T	p.Ser47Ile	missense	Exon 3 of 12	NP_653172.2	Q96LI5-1
	CNOT6L	NM_001387842.1		c.323G>T	p.Ser108Ile	missense	Exon 4 of 13	NP_001374771.1
	CNOT6L	NM_001387843.1		c.323G>T	p.Ser108Ile	missense	Exon 4 of 13	NP_001374772.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT6L	ENST00000504123.7	TSL:2 MANE Select	c.140G>T	p.Ser47Ile	missense	Exon 3 of 12	ENSP00000424896.1	Q96LI5-1
	CNOT6L	ENST00000873612.1		c.140G>T	p.Ser47Ile	missense	Exon 3 of 12	ENSP00000543671.1
	CNOT6L	ENST00000512485.6	TSL:5	c.125G>T	p.Ser42Ile	missense	Exon 3 of 12	ENSP00000425571.2	H0Y9Z5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434746 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 713040

⚠️ 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: 31782

American (AMR) AF: 0.00 AC: 0 AN: 38644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24898

East Asian (EAS) AF: 0.00 AC: 0 AN: 38762

South Asian (SAS) AF: 0.00 AC: 0 AN: 81860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52786

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101188

Other (OTH) AF: 0.00 AC: 0 AN: 59184

⚠️ 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	Uncertain	0.35
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.076
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.52
Sift	Benign	0.069	T
Sift4G	Uncertain	0.056	T
Polyphen		0.033	B
Vest4		0.51
MutPred		0.44		Loss of disorder (P = 0.0127)
MVP		0.50
ClinPred		0.98	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.57
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs766542626; hg19: chr4-78695858;