22-17542424-C-T

Variant names:

• chr22-17542424-C-T
• rs2147031368
• NM_001290047.2:c.2281C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001290047.2(CECR2):​c.2281C>T​(p.Arg761*) variant causes a stop gained 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CECR2 NM_001290047.2 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 1.82
• Publications: 0 publications found

Genes affected

CECR2 (HGNC:1840): (CECR2 histone acetyl-lysine reader) This gene encodes a bromodomain-containing protein that is involved in chromatin remodeling, and may additionally play a role in DNA damage response. The encoded protein functions as part of an ATP-dependent complex that is involved in neurulation. This gene is a candidate gene for Cat Eye Syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

ENSG00000286195 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 22-17542424-C-T is Pathogenic according to our data. Variant chr22-17542424-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1684511.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290047.2. 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
	CECR2	NM_001290047.2	MANE Select	c.2281C>T	p.Arg761*	stop_gained	Exon 16 of 19	NP_001276976.1	Q9BXF3-3
	CECR2	NM_001290046.2		c.1792C>T	p.Arg598*	stop_gained	Exon 16 of 19	NP_001276975.1	B7WPH3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CECR2	ENST00000262608.13	TSL:1 MANE Select	c.2281C>T	p.Arg761*	stop_gained	Exon 16 of 19	ENSP00000262608.11	Q9BXF3-3
	CECR2	ENST00000400585.7	TSL:1	c.1792C>T	p.Arg598*	stop_gained	Exon 16 of 19	ENSP00000383428.2	B7WPH3
	CECR2	ENST00000342247.10	TSL:5	c.2341C>T	p.Arg781*	stop_gained	Exon 17 of 20	ENSP00000341219.6	Q9BXF3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	CECR2-related neurodevelopmental disorder (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		1.8
Vest4		0.29
GERP RS		4.4
Mutation Taster		=12/188	disease causing (fs/PTC)

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: rs2147031368; hg19: chr22-18022113; COSMIC: COSV52837713;