12-70319329-TGTCTCAGT-ACCATCTACA

Variant names:

• chr12-70319329-TGTCTCAGT-ACCATCTACA
• NM_014515.7:c.203_211delTGTCTCAGTinsACCATCTACA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_014515.7(CNOT2):​c.203_211delTGTCTCAGTinsACCATCTACA​(p.Leu68HisfsTer70) variant causes a frameshift, 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNOT2 NM_014515.7 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.26
• Publications: 0 publications found

Genes affected

CNOT2 (HGNC:7878): (CCR4-NOT transcription complex subunit 2) This gene encodes a subunit of the multi-component CCR4-NOT complex. The CCR4-NOT complex regulates mRNA synthesis and degradation and is also thought to be involved in mRNA splicing, transport and localization. The encoded protein interacts with histone deacetylases and functions as a repressor of polymerase II transcription. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Dec 2010]

CNOT2 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-70319329-TGTCTCAGT-ACCATCTACA is Pathogenic according to our data. Variant chr12-70319329-TGTCTCAGT-ACCATCTACA is described in ClinVar as Pathogenic. ClinVar VariationId is 3369381.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014515.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT2	NM_014515.7	MANE Select	c.203_211delTGTCTCAGTinsACCATCTACA	p.Leu68HisfsTer70	frameshift missense	Exon 4 of 16	NP_055330.1	Q9NZN8-1
	CNOT2	NM_001199302.2		c.203_211delTGTCTCAGTinsACCATCTACA	p.Leu68HisfsTer70	frameshift missense	Exon 5 of 17	NP_001186231.1	Q9NZN8-1
	CNOT2	NM_001199303.2		c.203_211delTGTCTCAGTinsACCATCTACA	p.Leu68HisfsTer70	frameshift missense	Exon 4 of 16	NP_001186232.1	Q9NZN8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT2	ENST00000229195.8	TSL:1 MANE Select	c.203_211delTGTCTCAGTinsACCATCTACA	p.Leu68HisfsTer70	frameshift missense	Exon 4 of 16	ENSP00000229195.3	Q9NZN8-1
	CNOT2	ENST00000418359.7	TSL:1	c.203_211delTGTCTCAGTinsACCATCTACA	p.Leu68HisfsTer70	frameshift missense	Exon 5 of 17	ENSP00000412091.3	Q9NZN8-1
	CNOT2	ENST00000548159.5	TSL:1	c.176_184delTGTCTCAGTinsACCATCTACA	p.Leu59HisfsTer70	frameshift missense	Exon 5 of 17	ENSP00000449659.1	F8VV52

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr12-70713109;