16-58553833-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_016284.5(CNOT1):​c.2919G>A​(p.Gln973Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,608,122 control chromosomes in the GnomAD database, including 90,358 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12973 hom., cov: 32)
  • Exomes 𝑓: 0.31 (77385 hom.)
• Consequence: CNOT1 NM_016284.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 16-58553833-C-T is Benign according to our data. Variant chr16-58553833-C-T is described in ClinVar as Benign. ClinVar VariationId is 1217378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.76 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.583 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016284.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT1	NM_016284.5	MANE Select	c.2919G>A	p.Gln973Gln	synonymous	Exon 22 of 49	NP_057368.3
	CNOT1	NM_001265612.2		c.2904G>A	p.Gln968Gln	synonymous	Exon 22 of 49	NP_001252541.1
	CNOT1	NM_206999.3		c.2919G>A	p.Gln973Gln	synonymous	Exon 22 of 31	NP_996882.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT1	ENST00000317147.10	TSL:1 MANE Select	c.2919G>A	p.Gln973Gln	synonymous	Exon 22 of 49	ENSP00000320949.5
	CNOT1	ENST00000569240.5	TSL:1	c.2904G>A	p.Gln968Gln	synonymous	Exon 22 of 49	ENSP00000455635.1
	CNOT1	ENST00000441024.6	TSL:1	c.2919G>A	p.Gln973Gln	synonymous	Exon 22 of 31	ENSP00000413113.2

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59294 AN: 151958 Hom.: 12950 Cov.: 32

Gnomad AFR AF: 0.589

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.384

GnomAD2 exomes AF: 0.352 AC: 87032 AN: 246930 AF XY: 0.352

Gnomad AFR exome AF: 0.603

Gnomad AMR exome AF: 0.299

Gnomad ASJ exome AF: 0.373

Gnomad EAS exome AF: 0.565

Gnomad FIN exome AF: 0.256

Gnomad NFE exome AF: 0.297

Gnomad OTH exome AF: 0.329

GnomAD4 exome AF: 0.314 AC: 457838 AN: 1456046 Hom.: 77385 Cov.: 33 AF XY: 0.317 AC XY: 229886 AN XY: 724252

African (AFR) AF: 0.606 AC: 20014 AN: 33028

American (AMR) AF: 0.306 AC: 13450 AN: 44000

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 9781 AN: 25988

East Asian (EAS) AF: 0.608 AC: 23805 AN: 39158

South Asian (SAS) AF: 0.427 AC: 36386 AN: 85120

European-Finnish (FIN) AF: 0.257 AC: 13620 AN: 52946

Middle Eastern (MID) AF: 0.434 AC: 2495 AN: 5744

European-Non Finnish (NFE) AF: 0.286 AC: 317763 AN: 1109904

Other (OTH) AF: 0.341 AC: 20524 AN: 60158

GnomAD4 genome AF: 0.390 AC: 59361 AN: 152076 Hom.: 12973 Cov.: 32 AF XY: 0.391 AC XY: 29099 AN XY: 74348

African (AFR) AF: 0.590 AC: 24462 AN: 41486

American (AMR) AF: 0.322 AC: 4910 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 1315 AN: 3472

East Asian (EAS) AF: 0.573 AC: 2960 AN: 5170

South Asian (SAS) AF: 0.428 AC: 2064 AN: 4822

European-Finnish (FIN) AF: 0.266 AC: 2811 AN: 10574

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.291 AC: 19754 AN: 67972

Other (OTH) AF: 0.384 AC: 809 AN: 2108

Alfa AF: 0.340 Hom.: 21559

Bravo AF: 0.403

Asia WGS AF: 0.485 AC: 1686 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	CNOT1-related disorder (1)
-	-	1	Holoprosencephaly 12 with or without pancreatic agenesis (1)
-	-	1	Vissers-Bodmer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	9.2
DANN	Benign	0.66
PhyloP100		1.8
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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; COSMIC: COSV108079449; COSMIC: COSV108079449;