rs11866002

Variant names:

• chr16-58553833-C-G
• rs11866002
• NM_016284.5:c.2919G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-58553833-C-G
• chr16-58553833-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016284.5(CNOT1):​c.2919G>C​(p.Gln973His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q973Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNOT1 NM_016284.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.76
• Publications: 41 publications found

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]

CNOT1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• holoprosencephaly 12 with or without pancreatic agenesis

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
• Vissers-Bodmer syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT1	NM_016284.5	c.2919G>C	p.Gln973His	missense_variant	Exon 22 of 49	ENST00000317147.10	NP_057368.3
CNOT1	NM_001265612.2	c.2904G>C	p.Gln968His	missense_variant	Exon 22 of 49		NP_001252541.1
CNOT1	NM_206999.3	c.2919G>C	p.Gln973His	missense_variant	Exon 22 of 31		NP_996882.1
CNOT1	NR_049763.2	n.3177G>C		non_coding_transcript_exon_variant	Exon 22 of 50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT1	ENST00000317147.10	c.2919G>C	p.Gln973His	missense_variant	Exon 22 of 49	1	NM_016284.5	ENSP00000320949.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.5	L;.;L
PhyloP100		1.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0080	D;D;D
Sift4G	Benign	0.068	T;T;D
Polyphen		0.98	D;D;D
Vest4		0.69
MutPred		0.30		Gain of catalytic residue at L975 (P = 0.1308);.;Gain of catalytic residue at L975 (P = 0.1308);
MVP		0.47
MPC		2.2
ClinPred		0.91	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.56
Mutation Taster		=31/69	disease causing

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

Other links and lift over

dbSNP: rs11866002; hg19: chr16-58587737;