4-77729055-T-G

Position:

• chr4-77729055-T-G

Variant summary

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

The NM_144571.3(CNOT6L):​c.1051A>C​(p.Lys351Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNOT6L NM_144571.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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]

CNOT6L (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
CNOT6L	NM_144571.3	c.1051A>C	p.Lys351Gln	missense_variant	10/12	ENST00000504123.7	NP_653172.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNOT6L	ENST00000504123.7	c.1051A>C	p.Lys351Gln	missense_variant	10/12	2	NM_144571.3	ENSP00000424896.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jul 27, 2024

The c.1051A>C (p.K351Q) alteration is located in exon 10 (coding exon 10) of the CNOT6L gene. This alteration results from a A to C substitution at nucleotide position 1051, causing the lysine (K) at amino acid position 351 to be replaced by a glutamine (Q). 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	0.10
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	.;T;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.34	.;N;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.60	.;N;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.40	.;T;.;.
Sift4G	Benign	0.50	.;T;.;.
Polyphen		0.0020	.;B;.;.
Vest4		0.30
MutPred		0.53		.;Gain of catalytic residue at K351 (P = 0.0095);.;.;
MVP		0.41
ClinPred		0.67	D
GERP RS		5.7
Varity_R		0.51
gMVP		0.58

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: rs1722165687; hg19: chr4-78650209;