20-46371916-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BS1_Supporting

The NM_133171.5(ELMO2):c.1470C>A(p.Asn490Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000849 in 1,614,198 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 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: ELMO2 NM_133171.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.17

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ELMO2
• BP4: Computational evidence support a benign effect (MetaRNN=0.15045637).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00008 (117/1461858) while in subpopulation MID AF= 0.00122 (7/5744). AF 95% confidence interval is 0.000572. There are 0 homozygotes in gnomad4_exome. There are 57 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELMO2	NM_133171.5	c.1470C>A	p.Asn490Lys	missense_variant	17/22	ENST00000290246.11
LOC124904917	XR_007067614.1	n.182+7196G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELMO2	ENST00000290246.11	c.1470C>A	p.Asn490Lys	missense_variant	17/22	1	NM_133171.5	P4
	ENST00000651935.1	n.151+7196G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000676 AC: 17 AN: 251466 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135904

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.0000800 AC: 117 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.0000784 AC XY: 57 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000755

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74492

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000456 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2023

The c.1470C>A (p.N490K) alteration is located in exon 17 (coding exon 15) of the ELMO2 gene. This alteration results from a C to A substitution at nucleotide position 1470, causing the asparagine (N) at amino acid position 490 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.59
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.067	T;.;.;T;.
Eigen	Benign	-0.054
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.44	N;N;N;N;N
REVEL	Benign	0.070
Sift	Benign	0.25	T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T
Polyphen		0.010	B;.;.;B;.
Vest4		0.30
MVP		0.43
MPC		0.89
ClinPred		0.024	T
GERP RS		4.6
Varity_R		0.34
gMVP		0.14

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: rs574674005; hg19: chr20-45000555;