1-23510010-G-T

Variant names:

• chr1-23510010-G-T
• rs886819893
• NM_004091.4:c.1184C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004091.4(E2F2):​c.1184C>A​(p.Ala395Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A395V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: E2F2 NM_004091.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.88
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061221182).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004091.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	E2F2	NM_004091.4	MANE Select	c.1184C>A	p.Ala395Glu	missense	Exon 7 of 7	NP_004082.1	Q14209

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	E2F2	ENST00000361729.3	TSL:1 MANE Select	c.1184C>A	p.Ala395Glu	missense	Exon 7 of 7	ENSP00000355249.2	Q14209
	E2F2	ENST00000915331.1		c.1178C>A	p.Ala393Glu	missense	Exon 7 of 7	ENSP00000585390.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461420 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726974

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111902

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.1
DANN	Benign	0.52
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.092	N
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.97	L
PhyloP100		2.9
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.041
Sift	Benign	0.89	T
Sift4G	Benign	0.70	T
Polyphen		0.36	B
Vest4		0.051
MutPred		0.38		Gain of solvent accessibility (P = 0.005)
MVP		0.19
MPC		0.37
ClinPred		0.12	T
GERP RS		2.5
Varity_R		0.067
gMVP		0.26
Mutation Taster		=99/1	polymorphism

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

dbSNP: rs886819893; hg19: chr1-23836502;