Variant 10-11329003-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP2PP3PP5_Very_Strong

The NM_001326342.2(CELF2):c.1516C>T(p.Arg506Cys) variant causes a missense change. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R506G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

CELF2
NM_001326342.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 3.93

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 links:

CELF2-AS1 (HGNC:):

CELF2-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-11329003-C-G is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CELF2. . Trascript score misZ 4.1385 (greater than threshold 3.09). GenCC has associacion of gene with undetermined early-onset epileptic encephalopathy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy 97.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.806

PP5

Variant 10-11329003-C-T is Pathogenic according to our data. Variant chr10-11329003-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1693106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CELF2	NM_001326342.2 linkuse as main transcript	c.1516C>T	p.Arg506Cys	missense_variant	13/13	ENST00000633077.2	NP_001313271.1
CELF2-AS1	NR_126062.1 linkuse as main transcript	n.98-5336G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CELF2	ENST00000633077.2 linkuse as main transcript	c.1516C>T	p.Arg506Cys	missense_variant	13/13	1	NM_001326342.2	ENSP00000488690	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Apr 24, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.;T;T;T;T;.;.;.;.;.;.;.;T;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.99

D;.;D;.;D;D;.;D;D;.;.;D;D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.81

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.3

.;.;.;M;M;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-7.5

.;.;.;D;.;.;.;D;.;.;D;.;.;.;.

REVEL

Uncertain

0.44

Sift

Pathogenic

0.0

.;.;.;D;.;.;.;D;.;.;D;.;.;.;.

Sift4G

Pathogenic

0.0

.;.;.;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0, 1.0

.;.;.;D;D;.;D;D;.;.;.;.;.;.;.

Vest4

0.76, 0.75, 0.75, 0.73, 0.75, 0.74, 0.74, 0.75, 0.75, 0.71, 0.73

MutPred

0.64

.;.;.;.;.;.;Loss of disorder (P = 0.0245);Loss of disorder (P = 0.0245);.;.;.;.;.;.;.;

MVP

0.71

ClinPred

1.0

GERP RS

5.0

Varity_R

0.81

gMVP

0.92

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over