chr10-11165632-A-G

Variant names:

• chr10-11165632-A-G
• NM_001326342.2:c.221A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001326342.2(CELF2):​c.221A>G​(p.Tyr74Cys) 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 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: 9.16
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy 97

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CELF2	NM_001326342.2	c.221A>G	p.Tyr74Cys	missense_variant	Exon 2 of 13	ENST00000633077.2	NP_001313271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CELF2	ENST00000633077.2	c.221A>G	p.Tyr74Cys	missense_variant	Exon 2 of 13	1	NM_001326342.2	ENSP00000488690.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder Uncertain:1

Jun 19, 2024

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Tyr74Cys variant in CELF2 was identified by our study in 1 individual with a neurodevelopmental disorder. While this gene is still lacking sufficient evidence to establish a gene-disease relationship, we believe this is a possible novel gene candidate for neurodevelopmental disorders. Given the limited information about this gene-disease relationship, the significance of the p.Tyr74Cys variant is uncertain. If you have any additional information about functional evidence or other individuals with this phenotype that also have variants in CELF2 we encourage you to reach out to us. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T;.;T;T;T;T;.;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;.;D;.;D;D;.;D;D;.;.;D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;.;.;L;L;.;.;.;.;.;.;.;.;.;.
PhyloP100		9.2
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.7	.;.;.;D;.;.;.;D;.;.;D;D;.;.;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	.;.;.;D;.;.;.;D;.;.;D;D;.;.;D
Sift4G	Uncertain	0.040	.;.;.;D;D;D;D;D;D;D;D;D;D;T;D
Polyphen		0.99, 0.99	.;.;.;D;D;.;D;D;.;.;.;.;.;.;.
Vest4		0.76, 0.76, 0.76, 0.75, 0.76, 0.76, 0.72
MutPred		0.42		.;.;.;.;.;.;Loss of phosphorylation at Y74 (P = 0.076);Loss of phosphorylation at Y74 (P = 0.076);Loss of phosphorylation at Y74 (P = 0.076);.;.;.;.;.;.;
MVP		0.77
ClinPred		0.99	D
GERP RS		5.5
PromoterAI		0.0088	Neutral
Varity_R		0.68
gMVP		0.81
Mutation Taster		=7/93	disease causing

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

Other links and lift over

hg19: chr10-11207595;