NM_016284.5:c.6970A>C

Variant names:

• chr16-58521265-T-G
• NM_016284.5:c.6970A>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_016284.5(CNOT1):​c.6970A>C​(p.Ile2324Leu) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNOT1 NM_016284.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.82

Genes affected

CNOT1 (HGNC:7877): (CCR4-NOT transcription complex subunit 1) Enables armadillo repeat domain binding activity; molecular adaptor activity; and nuclear receptor binding activity. Contributes to poly(A)-specific ribonuclease activity. Involved in several processes, including negative regulation of signal transduction; positive regulation of cytoplasmic mRNA processing body assembly; and regulation of gene expression. Located in P-body and cytosol. Part of CCR4-NOT complex. Implicated in holoprosencephaly. [provided by Alliance of Genome Resources, Apr 2022]

SETD6 (HGNC:26116): (SET domain containing 6, protein lysine methyltransferase) This gene encodes a methyltransferase that adds a methyl group to the histone H2AZ, which is involved in nuclear receptor-dependent transcription. The protein also interacts with several endogenous proteins which are involved in nuclear hormone receptor signaling. A related pseudogene is located on chromosome 2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-58521265-T-G is Pathogenic according to our data. Variant chr16-58521265-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2505815.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT1	NM_016284.5	c.6970A>C	p.Ile2324Leu	missense_variant	Exon 48 of 49	ENST00000317147.10	NP_057368.3
SETD6	NM_001160305.4	c.*2236T>G		3_prime_UTR_variant	Exon 8 of 8	ENST00000219315.9	NP_001153777.1
CNOT1	NM_001265612.2	c.6955A>C	p.Ile2319Leu	missense_variant	Exon 48 of 49		NP_001252541.1
CNOT1	NR_049763.2	n.7411A>C		non_coding_transcript_exon_variant	Exon 49 of 50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT1	ENST00000317147.10	c.6970A>C	p.Ile2324Leu	missense_variant	Exon 48 of 49	1	NM_016284.5	ENSP00000320949.5
SETD6	ENST00000219315.9	c.*2236T>G		3_prime_UTR_variant	Exon 8 of 8	1	NM_001160305.4	ENSP00000219315.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 13, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Pathogenic	2.9	M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.27
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.98	D;P
Vest4		0.72
MutPred		0.67		Loss of catalytic residue at L2329 (P = 0.0447);.;
MVP		0.61
MPC		1.7
ClinPred		0.89	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.68
gMVP		0.68

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: chr16-58555169;