10-11314177-A-T

Position:

• chr10-11314177-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001326342.2(CELF2):​c.1015A>T​(p.Met339Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CELF2 NM_001326342.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.98

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40737128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CELF2	NM_001326342.2	c.1015A>T	p.Met339Leu	missense_variant	10/13	ENST00000633077.2	NP_001313271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CELF2	ENST00000633077.2	c.1015A>T	p.Met339Leu	missense_variant	10/13	1	NM_001326342.2	ENSP00000488690.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 14 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Jun 22, 2023

The observed missense c.994A>T (p.Met332Leu) variant in CELF2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Met332Leu variant is absent in gnomAD Exomes. This variant has not been submitted to the ClinVar database. Computational evidence (Polyphen - Benign, SIFT - Tolerated and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid of p.Met332Leu in CELF2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Met at position 332 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Benign	0.0027	T;.;T;T;T;T;.;.;.;.;.;.;.;T;.
Eigen	Benign	0.040
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;.;D;.;D;D;.;D;D;.;.;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.4	.;.;.;L;L;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.070	.;.;.;N;.;.;.;N;.;.;N;N;.;.;N
REVEL	Uncertain	0.29
Sift	Benign	0.56	.;.;.;T;.;.;.;T;.;.;T;T;.;.;T
Sift4G	Benign	1.0	.;.;.;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.17	.;.;.;B;B;.;B;B;.;.;.;.;.;.;.
Vest4		0.54, 0.54, 0.58, 0.57, 0.57, 0.57, 0.57, 0.56, 0.52
MutPred		0.34		.;.;.;.;.;.;Loss of catalytic residue at M339 (P = 0.0055);Loss of catalytic residue at M339 (P = 0.0055);Loss of catalytic residue at M339 (P = 0.0055);.;.;.;.;.;.;
MVP		0.92
ClinPred		0.90	D
GERP RS		5.4
Varity_R		0.28
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr10-11356140;