chr18-2890770-G-A

Position:

• chr18-2890770-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032048.3(EMILIN2):​c.643G>A​(p.Ala215Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0034 in 1,613,752 control chromosomes in the GnomAD database, including 173 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.018 (80 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (93 hom.)
• Consequence: EMILIN2 NM_032048.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.128

Genes affected

EMILIN2 (HGNC:19881): (elastin microfibril interfacer 2) Predicted to enable extracellular matrix constituent conferring elasticity. Predicted to be involved in cell adhesion. Located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

LPIN2 (HGNC:14450): (lipin 2) Mouse studies suggest that this gene functions during normal adipose tissue development and may play a role in human triglyceride metabolism. This gene represents a candidate gene for human lipodystrophy, characterized by loss of body fat, fatty liver, hypertriglyceridemia, and insulin resistance. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00142169).
• BP6: Variant 18-2890770-G-A is Benign according to our data. Variant chr18-2890770-G-A is described in ClinVar as [Benign]. Clinvar id is 781350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EMILIN2	NM_032048.3	c.643G>A	p.Ala215Thr	missense_variant	4/8	ENST00000254528.4	NP_114437.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EMILIN2	ENST00000254528.4	c.643G>A	p.Ala215Thr	missense_variant	4/8	1	NM_032048.3	ENSP00000254528	P1
LPIN2	ENST00000697039.1	c.2547-5336C>T		intron_variant				ENSP00000513061

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2721 AN: 152072 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.0627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00481 AC: 1208 AN: 250938 Hom.: 39 AF XY: 0.00352 AC XY: 478 AN XY: 135692

Gnomad AFR exome AF: 0.0691

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00188 AC: 2755 AN: 1461562 Hom.: 93 Cov.: 30 AF XY: 0.00160 AC XY: 1160 AN XY: 727034

Gnomad4 AFR exome AF: 0.0683

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000863

Gnomad4 OTH exome AF: 0.00409

GnomAD4 genome AF: 0.0180 AC: 2734 AN: 152190 Hom.: 80 Cov.: 32 AF XY: 0.0172 AC XY: 1277 AN XY: 74400

Gnomad4 AFR AF: 0.0629

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00395 Hom.: 19

Bravo AF: 0.0206

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0649 AC: 286

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00598 AC: 726

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

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	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.15
DANN	Benign	0.13
DEOGEN2	Benign	0.0052	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.17	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.044
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.044
MVP		0.16
MPC		0.084
ClinPred		0.00030	T
GERP RS		-0.012
Varity_R		0.028
gMVP		0.10

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: rs16943977; hg19: chr18-2890768;