Genetic Variant CELF2:p.Met1? (chr10-11018091-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_001326342.2(CELF2):c.2T>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000015 in 1,330,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

CELF2
NM_001326342.2 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.94

Publications

0 publications found

Variant links:

Genes affected

CELF2 (HGNC:2550): (CUGBP Elav-like family member 2) Members of the CELF/BRUNOL protein family contain two N-terminal RNA recognition motif (RRM) domains, one C-terminal RRM domain, and a divergent segment of 160-230 aa between the second and third RRM domains. Members of this protein family regulate pre-mRNA alternative splicing and may also be involved in mRNA editing, and translation. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

CELF2 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy 97
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

CELF2 links:

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ACMG classification

Classification was made for transcript

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

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 13 codons. Genomic position: 11018126. Lost 0.024 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CELF2	NM_001326342.2 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 13	ENST00000633077.2	NP_001313271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CELF2	ENST00000633077.2 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 13	1	NM_001326342.2	ENSP00000488690.1		E9PC62

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000150

AC:

AN:

1330444

Hom.:

Cov.:

AF XY:

0.00000151

AC XY:

AN XY:

662390

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26860

American (AMR)

AF:

0.00

AC:

AN:

32544

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21616

East Asian (EAS)

AF:

0.00

AC:

AN:

27292

South Asian (SAS)

AF:

0.00

AC:

AN:

76678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5222

European-Non Finnish (NFE)

AF:

0.00000192

AC:

AN:

1039150

Other (OTH)

AF:

0.00

AC:

AN:

52502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Benign

0.93

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.90

.;D;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Benign

-0.71

PhyloP100

3.9

PROVEAN

Benign

-0.26

.;N;.

REVEL

Benign

0.20

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.018

B;B;.

Vest4

0.87

MutPred

1.0

Gain of catalytic residue at M1 (P = 0.0088);Gain of catalytic residue at M1 (P = 0.0088);Gain of catalytic residue at M1 (P = 0.0088);

MVP

0.70

ClinPred

0.80

GERP RS

3.0

PromoterAI

-0.11

Neutral

(source)

gMVP

0.40

Mutation Taster

=83/117

disease causing

(source)

Splicing

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

Publications

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10-11018091-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over