2-11451740-G-C

Variant names:

• chr2-11451740-G-C
• rs372426239
• NM_198256.4:c.447C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198256.4(E2F6):​c.447C>G​(p.Asp149Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000604 in 1,457,200 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: E2F6 NM_198256.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.762
• Publications: 0 publications found

Genes affected

E2F6 (HGNC:3120): (E2F transcription factor 6) This gene encodes a member of a family of transcription factors that play a crucial role in the control of the cell cycle. The protein encoded by this gene lacks the transactivation and tumor suppressor protein association domains found in other family members, and contains a modular suppression domain that functions in the inhibition of transcription. It interacts in a complex with chromatin modifying factors. There are pseudogenes for this gene on chromosomes 22 and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12847191).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198256.4. 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
	E2F6	NM_198256.4	MANE Select	c.447C>G	p.Asp149Glu	missense	Exon 4 of 7	NP_937987.2	O75461-1
	E2F6	NM_001278275.2		c.351C>G	p.Asp117Glu	missense	Exon 5 of 8	NP_001265204.1	O75461-3
	E2F6	NM_001278276.2		c.222C>G	p.Asp74Glu	missense	Exon 5 of 8	NP_001265205.1	O75461-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	E2F6	ENST00000381525.8	TSL:1 MANE Select	c.447C>G	p.Asp149Glu	missense	Exon 4 of 7	ENSP00000370936.3	O75461-1
	E2F6	ENST00000307236.8	TSL:1	c.351C>G	p.Asp117Glu	missense	Exon 5 of 8	ENSP00000302159.4	O75461-3
	E2F6	ENST00000542100.5	TSL:1	c.222C>G	p.Asp74Glu	missense	Exon 6 of 9	ENSP00000446315.1	O75461-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000207 AC: 5 AN: 241714 AF XY: 0.0000153

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000461

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000604 AC: 88 AN: 1457200 Hom.: 0 Cov.: 31 AF XY: 0.0000580 AC XY: 42 AN XY: 724466

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25990

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 85512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0000775 AC: 86 AN: 1109210

Other (OTH) AF: 0.0000332 AC: 2 AN: 60172

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.0000331 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Benign	0.76
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.76
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.28
Sift	Benign	0.54	T
Sift4G	Benign	0.49	T
Polyphen		0.60	P
Vest4		0.11
MutPred		0.32		Gain of disorder (P = 0.239)
MVP		0.68
MPC		0.86
ClinPred		0.13	T
GERP RS		2.8
Varity_R		0.096
gMVP		0.39
Mutation Taster		=81/19	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: rs372426239; hg19: chr2-11591866;