chr10-11329004-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP2PP3PP5_Moderate

The NM_001326342.2(CELF2):​c.1517G>T​(p.Arg506Leu) variant causes a missense change involving the alteration of a 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 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

7
7
5

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 10.0
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 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, 0.808
PP5
Variant 10-11329004-G-T is Pathogenic according to our data. Variant chr10-11329004-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2579922.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CELF2NM_001326342.2 linkuse as main transcriptc.1517G>T p.Arg506Leu missense_variant 13/13 ENST00000633077.2 NP_001313271.1
CELF2-AS1NR_126062.1 linkuse as main transcriptn.98-5337C>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CELF2ENST00000633077.2 linkuse as main transcriptc.1517G>T p.Arg506Leu missense_variant 13/131 NM_001326342.2 ENSP00000488690 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxMar 17, 2023Not 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 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Benign
0.14
T;.;T;T;T;T;.;.;.;.;.;.;.;T;.
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;.;D;.;D;D;.;D;D;.;.;D;D;D;D
M_CAP
Benign
0.060
D
MetaRNN
Pathogenic
0.81
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
.;.;.;L;L;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-6.5
.;.;.;D;.;.;.;D;.;.;D;.;.;.;.
REVEL
Uncertain
0.49
Sift
Uncertain
0.0010
.;.;.;D;.;.;.;D;.;.;D;.;.;.;.
Sift4G
Pathogenic
0.0
.;.;.;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.57, 0.88
.;.;.;P;P;.;P;P;.;.;.;.;.;.;.
Vest4
0.83, 0.88, 0.86, 0.89, 0.83, 0.82, 0.82, 0.88, 0.85, 0.84
MutPred
0.62
.;.;.;.;.;.;Loss of disorder (P = 0.0434);Loss of disorder (P = 0.0434);.;.;.;.;.;.;.;
MVP
0.88
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.76
gMVP
0.94

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-11370967; API