rs2361689

Positions:

• chr7-155462637-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001427.4(EN2):​c.952T>C​(p.Leu318Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,608,388 control chromosomes in the GnomAD database, including 92,113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10156 hom., cov: 33)
  • Exomes 𝑓: 0.33 (81957 hom.)
• Consequence: EN2 NM_001427.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.92

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 7-155462637-T-C is Benign according to our data. Variant chr7-155462637-T-C is described in ClinVar as [Benign]. Clinvar id is 1260669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.92 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EN2	NM_001427.4	c.952T>C	p.Leu318Leu	synonymous_variant	2/2	ENST00000297375.4	NP_001418.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EN2	ENST00000297375.4	c.952T>C	p.Leu318Leu	synonymous_variant	2/2	1	NM_001427.4	ENSP00000297375.4

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54708 AN: 151950 Hom.: 10135 Cov.: 33

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.421

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.327

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.366

GnomAD3 exomes AF: 0.362 AC: 85893 AN: 237086 Hom.: 16082 AF XY: 0.362 AC XY: 46477 AN XY: 128522

Gnomad AFR exome AF: 0.432

Gnomad AMR exome AF: 0.496

Gnomad ASJ exome AF: 0.373

Gnomad EAS exome AF: 0.220

Gnomad SAS exome AF: 0.440

Gnomad FIN exome AF: 0.312

Gnomad NFE exome AF: 0.321

Gnomad OTH exome AF: 0.361

GnomAD4 exome AF: 0.332 AC: 482957 AN: 1456320 Hom.: 81957 Cov.: 51 AF XY: 0.335 AC XY: 242339 AN XY: 724062

Gnomad4 AFR exome AF: 0.433

Gnomad4 AMR exome AF: 0.486

Gnomad4 ASJ exome AF: 0.375

Gnomad4 EAS exome AF: 0.242

Gnomad4 SAS exome AF: 0.441

Gnomad4 FIN exome AF: 0.305

Gnomad4 NFE exome AF: 0.317

Gnomad4 OTH exome AF: 0.342

GnomAD4 genome AF: 0.360 AC: 54762 AN: 152068 Hom.: 10156 Cov.: 33 AF XY: 0.361 AC XY: 26849 AN XY: 74316

Gnomad4 AFR AF: 0.428

Gnomad4 AMR AF: 0.422

Gnomad4 ASJ AF: 0.377

Gnomad4 EAS AF: 0.224

Gnomad4 SAS AF: 0.429

Gnomad4 FIN AF: 0.294

Gnomad4 NFE AF: 0.322

Gnomad4 OTH AF: 0.362

Alfa AF: 0.341 Hom.: 5687

Bravo AF: 0.371

Asia WGS AF: 0.329 AC: 1145 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.5
DANN	Benign	0.73

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: rs2361689; hg19: chr7-155255332; COSMIC: COSV52082670;