10-11321249-C-G

Position:

• chr10-11321249-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_001326342.2(CELF2):​c.1157C>G​(p.Thr386Arg) 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: 32)
• Consequence: CELF2 NM_001326342.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.87

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a region_of_interest Necessary for RNA-binding, TNNT2 exon 5 and NMDA R1 exon 21 inclusion (size 151) in uniprot entity CELF2_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001326342.2
• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2940761).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CELF2	NM_001326342.2	c.1157C>G	p.Thr386Arg	missense_variant	11/13	ENST00000633077.2
CELF2-AS1	NR_126062.1	n.196-2039G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CELF2	ENST00000633077.2	c.1157C>G	p.Thr386Arg	missense_variant	11/13	1	NM_001326342.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 30, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter 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	0.58
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T;.;T;T;T;T;.;.;.;.;.;.;.;T;.
Eigen	Benign	0.046
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.97	D;.;D;.;D;D;.;D;D;.;.;D;D;D;D
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;.;.;L;L;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.4	.;.;.;N;.;.;.;N;.;.;N;.;.;.;.
REVEL	Benign	0.13
Sift	Uncertain	0.022	.;.;.;D;.;.;.;T;.;.;T;.;.;.;.
Sift4G	Benign	0.35	.;.;.;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.64, 0.20	.;.;.;P;P;.;B;B;.;.;.;.;.;.;.
Vest4		0.68, 0.67, 0.70, 0.69, 0.69, 0.63, 0.69, 0.69, 0.69, 0.68, 0.58
MutPred		0.43		.;.;.;.;.;.;Gain of solvent accessibility (P = 0.0058);Gain of solvent accessibility (P = 0.0058);.;.;.;.;.;.;.;
MVP		0.62
ClinPred		0.57	D
GERP RS		5.3
Varity_R		0.25
gMVP		0.86

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: chr10-11363212;