7-155458504-G-C

Position:

• chr7-155458504-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001427.4(EN2):​c.127G>C​(p.Gly43Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000379 in 1,320,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: EN2 NM_001427.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.27

Genes affected

EN2 (HGNC:3343): (engrailed homeobox 2) Homeobox-containing genes are thought to have a role in controlling development. In Drosophila, the 'engrailed' (en) gene plays an important role during development in segmentation, where it is required for the formation of posterior compartments. Different mutations in the mouse homologs, En1 and En2, produced different developmental defects that frequently are lethal. The human engrailed homologs 1 and 2 encode homeodomain-containing proteins and have been implicated in the control of pattern formation during development of the central nervous system. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24662831).
• BS2: High AC in GnomAdExome4 at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EN2	NM_001427.4	c.127G>C	p.Gly43Arg	missense_variant	1/2	ENST00000297375.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EN2	ENST00000297375.4	c.127G>C	p.Gly43Arg	missense_variant	1/2	1	NM_001427.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000443

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000402 AC: 47 AN: 1169772 Hom.: 0 Cov.: 30 AF XY: 0.0000390 AC XY: 22 AN XY: 564088

Gnomad4 AFR exome AF: 0.0000428

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: 0.00

Gnomad4 NFE exome AF: 0.0000466

Gnomad4 OTH exome AF: 0.0000212

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151168 Hom.: 0 Cov.: 33 AF XY: 0.0000406 AC XY: 3 AN XY: 73842

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000443

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.96	N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.17
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.066	T
Polyphen		0.030	B
Vest4		0.24
MutPred		0.14		Gain of MoRF binding (P = 0.0442);
MVP		0.73
MPC		2.3
ClinPred		0.46	T
GERP RS		2.3
Varity_R		0.12
gMVP		0.24

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: rs1404661928; hg19: chr7-155251199;