1-23521045-G-A

Position:

• chr1-23521045-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000361729.3(E2F2):​c.605C>T​(p.Thr202Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,613,178 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (20 hom.)
• Consequence: E2F2 ENST00000361729.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.32

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036780536).
• BP6: Variant 1-23521045-G-A is Benign according to our data. Variant chr1-23521045-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 713748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00423 (6185/1460840) while in subpopulation MID AF= 0.0239 (137/5744). AF 95% confidence interval is 0.0206. There are 20 homozygotes in gnomad4_exome. There are 3063 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 468 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
E2F2	NM_004091.4	c.605C>T	p.Thr202Ile	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.605C>T	p.Thr202Ile	missense_variant	4/7	1	NM_004091.4	ENSP00000355249	P1

Frequencies

GnomAD3 genomes AF: 0.00307 AC: 468 AN: 152220 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00322 AC: 804 AN: 249764 Hom.: 6 AF XY: 0.00320 AC XY: 432 AN XY: 135008

Gnomad AFR exome AF: 0.00112

Gnomad AMR exome AF: 0.00470

Gnomad ASJ exome AF: 0.00210

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00462

Gnomad OTH exome AF: 0.00706

GnomAD4 exome AF: 0.00423 AC: 6185 AN: 1460840 Hom.: 20 Cov.: 32 AF XY: 0.00421 AC XY: 3063 AN XY: 726704

Gnomad4 AFR exome AF: 0.00156

Gnomad4 AMR exome AF: 0.00451

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00139

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00480

Gnomad4 OTH exome AF: 0.00481

GnomAD4 genome AF: 0.00307 AC: 468 AN: 152338 Hom.: 2 Cov.: 32 AF XY: 0.00267 AC XY: 199 AN XY: 74488

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00581

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00447

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00456 Hom.: 6

Bravo AF: 0.00314

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00288 AC: 350

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00546

EpiControl AF: 0.00566

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.43	N
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.0037	T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.59	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.26
Sift	Benign	0.11	T
Sift4G	Benign	0.17	T
Polyphen		0.97	D
Vest4		0.055
MVP		0.62
MPC		0.40
ClinPred		0.023	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.039
gMVP		0.19

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: rs116694174; hg19: chr1-23847537;