rs2229297

Positions:

• chr1-23521037-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004091.4(E2F2):​c.613G>A​(p.Gly205Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00978 in 1,613,476 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0070 (10 hom., cov: 32)
  • Exomes 𝑓: 0.010 (91 hom.)
• Consequence: E2F2 NM_004091.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.807

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004575819).
• BS2: High AC in GnomAd4 at 1067 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
E2F2	NM_004091.4	c.613G>A	p.Gly205Arg	missense_variant	4/7	ENST00000361729.3	NP_004082.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
E2F2	ENST00000361729.3	c.613G>A	p.Gly205Arg	missense_variant	4/7	1	NM_004091.4	ENSP00000355249	P1

Frequencies

GnomAD3 genomes AF: 0.00702 AC: 1068 AN: 152210 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00737 AC: 1845 AN: 250308 Hom.: 10 AF XY: 0.00788 AC XY: 1067 AN XY: 135324

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00230

Gnomad ASJ exome AF: 0.00458

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.0139

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00770

GnomAD4 exome AF: 0.0101 AC: 14705 AN: 1461148 Hom.: 91 Cov.: 32 AF XY: 0.0104 AC XY: 7546 AN XY: 726858

Gnomad4 AFR exome AF: 0.00129

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.00483

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0134

Gnomad4 FIN exome AF: 0.00202

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.00863

GnomAD4 genome AF: 0.00700 AC: 1067 AN: 152328 Hom.: 10 Cov.: 32 AF XY: 0.00623 AC XY: 464 AN XY: 74480

Gnomad4 AFR AF: 0.00188

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.0119

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.0105 Hom.: 22

Bravo AF: 0.00665

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0124 AC: 107

ExAC AF: 0.00789 AC: 958

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.00981

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.91
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.28	N
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.068
Sift	Benign	0.13	T
Sift4G	Benign	0.42	T
Polyphen		0.0070	B
Vest4		0.12
MutPred		0.10		Gain of solvent accessibility (P = 0.0306);
MVP		0.22
MPC		0.39
ClinPred		0.0028	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.040
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2229297; hg19: chr1-23847529;