rs749569923

Variant names:

• chr2-118846940-T-G
• rs749569923
• NM_001426.4:c.228A>C

Your query was ambiguous. Multiple possible variants found:

• chr2-118846940-T-G
• chr2-118846940-T-A
• chr2-118846940-T-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001426.4(EN1):​c.228A>C​(p.Pro76Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0042 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EN1 NM_001426.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.314
• Publications: 0 publications found

Genes affected

EN1 (HGNC:3342): (engrailed homeobox 1) 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]

EN1 Gene-Disease associations (from GenCC):

• ENDOVE syndrome, limb-only type

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-118846940-T-G is Benign according to our data. Variant chr2-118846940-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 402827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.314 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001426.4. 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
	EN1	NM_001426.4	MANE Select	c.228A>C	p.Pro76Pro	synonymous	Exon 1 of 2	NP_001417.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EN1	ENST00000295206.7	TSL:2 MANE Select	c.228A>C	p.Pro76Pro	synonymous	Exon 1 of 2	ENSP00000295206.5	Q05925

Frequencies

GnomAD3 genomes AF: 0.000336 AC: 13 AN: 38712 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000937

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000362

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000393

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00422 AC: 455 AN: 107834 Hom.: 0 Cov.: 0 AF XY: 0.00410 AC XY: 239 AN XY: 58240

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00448 AC: 8 AN: 1786

American (AMR) AF: 0.00219 AC: 11 AN: 5028

Ashkenazi Jewish (ASJ) AF: 0.00306 AC: 13 AN: 4250

East Asian (EAS) AF: 0.00657 AC: 14 AN: 2132

South Asian (SAS) AF: 0.00326 AC: 53 AN: 16260

European-Finnish (FIN) AF: 0.00632 AC: 25 AN: 3956

Middle Eastern (MID) AF: 0.00649 AC: 2 AN: 308

European-Non Finnish (NFE) AF: 0.00427 AC: 297 AN: 69594

Other (OTH) AF: 0.00708 AC: 32 AN: 4520

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000336 AC: 13 AN: 38722 Hom.: 0 Cov.: 0 AF XY: 0.000346 AC XY: 7 AN XY: 20218

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000936 AC: 1 AN: 10686

American (AMR) AF: 0.000361 AC: 2 AN: 5536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 884

East Asian (EAS) AF: 0.00 AC: 0 AN: 1394

South Asian (SAS) AF: 0.00 AC: 0 AN: 1038

European-Finnish (FIN) AF: 0.000393 AC: 1 AN: 2546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 120

European-Non Finnish (NFE) AF: 0.000573 AC: 9 AN: 15694

Other (OTH) AF: 0.00 AC: 0 AN: 660

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0190 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	11
DANN	Benign	0.36
PhyloP100		0.31
Mutation Taster		=100/0	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: rs749569923; hg19: chr2-119604516; COSMIC: COSV54632454; COSMIC: COSV54632454;