Genetic Variant NM_001290047.2:c.4254C>A (chr22-17549541-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001290047.2(CECR2):c.4254C>A(p.Phe1418Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CECR2
NM_001290047.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.04

Publications

0 publications found

Variant links:

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]

CECR2 links:

ENSG00000286195 (HGNC:):

ENSG00000286195 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19472116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CECR2	NM_001290047.2 link	c.4254C>A	p.Phe1418Leu	missense_variant	Exon 17 of 19	ENST00000262608.13	NP_001276976.1	Q9BXF3-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CECR2	ENST00000262608.13 link	c.4254C>A	p.Phe1418Leu	missense_variant	Exon 17 of 19	1	NM_001290047.2	ENSP00000262608.11		Q9BXF3-3A0A0R4J2E1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1444968

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

716918

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33152

American (AMR)

AF:

0.00

AC:

AN:

41836

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25708

East Asian (EAS)

AF:

0.00

AC:

AN:

39158

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83324

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52158

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103982

Other (OTH)

AF:

0.00

AC:

AN:

59904

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

.;T;.;T

Eigen

Benign

-0.063

Eigen_PC

Benign

-0.019

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.19

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

.;M;.;.

PhyloP100

1.0

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.8

N;.;.;.

REVEL

Benign

0.074

Sift

Uncertain

0.013

D;.;.;.

Sift4G

Benign

0.12

T;T;T;T

Polyphen

0.61

P;B;.;.

Vest4

0.36

MutPred

0.18

.;Gain of helix (P = 0.0325);.;.;

MVP

0.45

ClinPred

0.80

GERP RS

2.6

Varity_R

0.071

gMVP

0.098

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over