4-77720552-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_144571.3(CNOT6L):c.1547A>G(p.Asn516Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,613,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: CNOT6L NM_144571.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35

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

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CNOT6L
• BP4: Computational evidence support a benign effect (MetaRNN=0.17642239).
• BS2: High AC in GnomAd at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNOT6L	NM_144571.3	c.1547A>G	p.Asn516Ser	missense_variant	12/12	ENST00000504123.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNOT6L	ENST00000504123.7	c.1547A>G	p.Asn516Ser	missense_variant	12/12	2	NM_144571.3

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000165 AC: 41 AN: 248668 Hom.: 0 AF XY: 0.000171 AC XY: 23 AN XY: 134874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000285

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000333 AC: 486 AN: 1461194 Hom.: 0 Cov.: 31 AF XY: 0.000327 AC XY: 238 AN XY: 726884

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.000399

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74446

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000332 Hom.: 0

Bravo AF: 0.000140

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000365 AC: 3

ExAC AF: 0.000141 AC: 17

EpiCase AF: 0.000709

EpiControl AF: 0.000237

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

Aug 02, 2022

The c.1547A>G (p.N516S) alteration is located in exon 12 (coding exon 12) of the CNOT6L gene. This alteration results from a A to G substitution at nucleotide position 1547, causing the asparagine (N) at amino acid position 516 to be replaced by a serine (S). 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	0.069
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	-0.025
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Uncertain	0.15	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
Polyphen		0.0	.;B;.
Vest4		0.16
MVP		0.51
ClinPred		0.032	T
GERP RS		6.0
Varity_R		0.30
gMVP		0.37

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: rs200590761; hg19: chr4-78641706; COSMIC: COSV99362221;