Genetic Variant NM_133171.5:c.2080delC (chr20-46367442-AG-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_133171.5(ELMO2):c.2080delC(p.Leu694TrpfsTer127) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,461,128 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ELMO2
NM_133171.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.60

Publications

0 publications found

Variant links:

Genes affected

ELMO2 (HGNC:17233): (engulfment and cell motility 2) The protein encoded by this gene interacts with the dedicator of cyto-kinesis 1 protein. Similarity to a C. elegans protein suggests that this protein may function in phagocytosis of apoptotic cells and in cell migration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ELMO2 Gene-Disease associations (from GenCC):

primary intraosseous venous malformation
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
Ramon syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ELMO2 links:

ENSG00000273828 (HGNC:):

ENSG00000273828 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0384 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-46367442-AG-A is Pathogenic according to our data. Variant chr20-46367442-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 254193.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133171.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ELMO2	NM_133171.5	MANE Select	c.2080delC	p.Leu694TrpfsTer127	frameshift	Exon 22 of 22	NP_573403.1
ELMO2	NM_182764.3		c.2080delC	p.Leu694TrpfsTer127	frameshift	Exon 21 of 21	NP_877496.1
ELMO2	NM_001318253.2		c.1816delC	p.Leu606TrpfsTer127	frameshift	Exon 22 of 22	NP_001305182.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ELMO2	ENST00000290246.11	TSL:1 MANE Select	c.2080delC	p.Leu694TrpfsTer127	frameshift	Exon 22 of 22	ENSP00000290246.6
ELMO2	ENST00000396391.5	TSL:1	c.2080delC	p.Leu694TrpfsTer127	frameshift	Exon 21 of 21	ENSP00000379673.1
ELMO2	ENST00000372176.5	TSL:5	c.1816delC	p.Leu606TrpfsTer127	frameshift	Exon 22 of 22	ENSP00000361249.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000799

AC:

AN:

250182

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461128

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726830

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33436

American (AMR)

AF:

0.0000448

AC:

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39608

South Asian (SAS)

AF:

0.00

AC:

AN:

86128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111720

Other (OTH)

AF:

0.00

AC:

AN:

60374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary intraosseous venous malformation (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.6

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over