10-11288499-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001326342.2(CELF2):c.923A>G(p.Asn308Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00115 in 1,613,952 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: CELF2 NM_001326342.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.07

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 Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CELF2
• BP4: Computational evidence support a benign effect (MetaRNN=0.012553066).
• BP6: Variant 10-11288499-A-G is Benign according to our data. Variant chr10-11288499-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2640299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 111 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CELF2	NM_001326342.2	c.923A>G	p.Asn308Ser	missense_variant	9/13	ENST00000633077.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CELF2	ENST00000633077.2	c.923A>G	p.Asn308Ser	missense_variant	9/13	1	NM_001326342.2	P1

Frequencies

GnomAD3 genomes AF: 0.000730 AC: 111 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000835 AC: 208 AN: 249090 Hom.: 1 AF XY: 0.000805 AC XY: 109 AN XY: 135332

Gnomad AFR exome AF: 0.000453

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.000976

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00120 AC: 1751 AN: 1461686 Hom.: 2 Cov.: 30 AF XY: 0.00115 AC XY: 833 AN XY: 727146

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.00142

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.000729 AC: 111 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.000685 AC XY: 51 AN XY: 74458

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000965 Hom.: 0

Bravo AF: 0.000835

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000486 AC: 2

ESP6500EA AF: 0.00167 AC: 14

ExAC AF: 0.000802 AC: 97

EpiCase AF: 0.000654

EpiControl AF: 0.00160

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CELF2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

CELF2: PP2, BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.50
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.011	T;.;T;T;T;T;.;.;.;.;.;.;.;T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.0026
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D;.;D;.;D;D;.;D;D;.;.;D;D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.013	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
Polyphen		0.0050, 0.0010	.;.;.;B;B;.;B;B;.;.;.;.;.;.;.
Vest4		0.35, 0.35, 0.34, 0.35, 0.35, 0.35, 0.35, 0.34
MVP		0.45
ClinPred		0.024	T
GERP RS		4.8
Varity_R		0.071
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs41291249; hg19: chr10-11330462; COSMIC: COSV100258807;