Variant chr1-23520914-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000361729.3(E2F2):c.736A>G(p.Arg246Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000354 in 1,581,588 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

E2F2
ENST00000361729.3 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.33

Variant links:

Genes affected

E2F2 (HGNC:3114): (E2F transcription factor 2) The protein encoded by this gene is a member of the E2F family of transcription factors. The E2F family plays a crucial role in the control of cell cycle and action of tumor suppressor proteins and is also a target of the transforming proteins of small DNA tumor viruses. The E2F proteins contain several evolutionally conserved domains found in most members of the family. These domains include a DNA binding domain, a dimerization domain which determines interaction with the differentiation regulated transcription factor proteins (DP), a transactivation domain enriched in acidic amino acids, and a tumor suppressor protein association domain which is embedded within the transactivation domain. This protein and another 2 members, E2F1 and E2F3, have an additional cyclin binding domain. This protein binds specifically to retinoblastoma protein pRB in a cell-cycle dependent manner, and it exhibits overall 46% amino acid identity to E2F1. [provided by RefSeq, Jul 2008]

E2F2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
E2F2	NM_004091.4 linkuse as main transcript	c.736A>G	p.Arg246Gly	missense_variant, splice_region_variant	4/7	ENST00000361729.3	NP_004082.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
E2F2	ENST00000361729.3 linkuse as main transcript	c.736A>G	p.Arg246Gly	missense_variant, splice_region_variant	4/7	1	NM_004091.4	ENSP00000355249	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000310

AC:

AN:

225708

Hom.:

AF XY:

0.0000408

AC XY:

AN XY:

122522

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000947

Gnomad NFE exome

AF:

0.0000480

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000378

AC:

AN:

1429444

Hom.:

Cov.:

AF XY:

0.0000408

AC XY:

AN XY:

709968

show subpopulations

Gnomad4 AFR exome

AF:

0.0000624

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000567

Gnomad4 NFE exome

AF:

0.0000438

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000279

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2024

The c.736A>G (p.R246G) alteration is located in exon 4 (coding exon 4) of the E2F2 gene. This alteration results from a A to G substitution at nucleotide position 736, causing the arginine (R) at amino acid position 246 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.93

M_CAP

Uncertain

0.092

MetaRNN

Uncertain

0.53

MetaSVM

Uncertain

0.39

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

0.87

PrimateAI

Benign

0.28

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.58

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0090

Polyphen

0.95

Vest4

0.53

MutPred

0.48

Loss of MoRF binding (P = 0.039);

MVP

0.82

MPC

0.65

ClinPred

0.60

GERP RS

4.7

Varity_R

0.69

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over