chr10-11329004-G-T

Position:

• chr10-11329004-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0

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-AS1 (HGNC:):

ACMG classification

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
CELF2	NM_001326342.2	c.1517G>T	p.Arg506Leu	missense_variant	13/13	ENST00000633077.2	NP_001313271.1
CELF2-AS1	NR_126062.1	n.98-5337C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CELF2	ENST00000633077.2	c.1517G>T	p.Arg506Leu	missense_variant	13/13	1	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

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 17, 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 -

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;