7-155458738-C-T

Variant names:

• chr7-155458738-C-T
• rs3735653
• NM_001427.4:c.361C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001427.4(EN2):​c.361C>T​(p.Leu121Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 1,370,062 control chromosomes in the GnomAD database, including 164,063 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.41 (14234 hom., cov: 32)
  • Exomes 𝑓: 0.49 (149829 hom.)
• Consequence: EN2 NM_001427.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 14 publications found

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]

EN2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9754937E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001427.4. 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
	EN2	NM_001427.4	MANE Select	c.361C>T	p.Leu121Phe	missense	Exon 1 of 2	NP_001418.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EN2	ENST00000297375.4	TSL:1 MANE Select	c.361C>T	p.Leu121Phe	missense	Exon 1 of 2	ENSP00000297375.4	P19622

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62151 AN: 151180 Hom.: 14230 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.614

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.627

Gnomad SAS AF: 0.482

Gnomad FIN AF: 0.486

Gnomad MID AF: 0.542

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.449

GnomAD2 exomes AF: 0.541 AC: 1277 AN: 2360 AF XY: 0.534

Gnomad AFR exome AF: 0.306

Gnomad AMR exome AF: 0.473

Gnomad ASJ exome AF: 0.605

Gnomad EAS exome AF: 0.732

Gnomad FIN exome AF: 0.500

Gnomad NFE exome AF: 0.533

Gnomad OTH exome AF: 0.522

GnomAD4 exome AF: 0.493 AC: 600676 AN: 1218772 Hom.: 149829 Cov.: 78 AF XY: 0.494 AC XY: 292877 AN XY: 592734

African (AFR) AF: 0.174 AC: 4098 AN: 23486

American (AMR) AF: 0.418 AC: 4036 AN: 9644

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 8787 AN: 16684

East Asian (EAS) AF: 0.626 AC: 17163 AN: 27404

South Asian (SAS) AF: 0.486 AC: 25567 AN: 52614

European-Finnish (FIN) AF: 0.474 AC: 13963 AN: 29466

Middle Eastern (MID) AF: 0.524 AC: 1826 AN: 3482

European-Non Finnish (NFE) AF: 0.498 AC: 500993 AN: 1005788

Other (OTH) AF: 0.483 AC: 24243 AN: 50204

GnomAD4 genome AF: 0.411 AC: 62171 AN: 151290 Hom.: 14234 Cov.: 32 AF XY: 0.413 AC XY: 30515 AN XY: 73962

African (AFR) AF: 0.191 AC: 7893 AN: 41316

American (AMR) AF: 0.428 AC: 6510 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 1795 AN: 3462

East Asian (EAS) AF: 0.627 AC: 3189 AN: 5086

South Asian (SAS) AF: 0.483 AC: 2322 AN: 4804

European-Finnish (FIN) AF: 0.486 AC: 5078 AN: 10442

Middle Eastern (MID) AF: 0.548 AC: 159 AN: 290

European-Non Finnish (NFE) AF: 0.498 AC: 33726 AN: 67684

Other (OTH) AF: 0.451 AC: 945 AN: 2094

Alfa AF: 0.438 Hom.: 1905

Bravo AF: 0.398

TwinsUK AF: 0.506 AC: 1877

ALSPAC AF: 0.513 AC: 1979

ExAC AF: 0.242 AC: 1195

Asia WGS AF: 0.511 AC: 1746 AN: 3418

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.71
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0000020	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.17
Sift	Benign	0.12	T
Sift4G	Benign	0.21	T
Polyphen		0.43	B
Vest4		0.038
MPC		2.0
ClinPred		0.0044	T
GERP RS		1.9
Varity_R		0.099
gMVP		0.089
Mutation Taster		=69/31	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: rs3735653; hg19: chr7-155251433; COSMIC: COSV52083358; COSMIC: COSV52083358;