18-2890855-C-A

Position:

• chr18-2890855-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032048.3(EMILIN2):​c.728C>A​(p.Thr243Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,613,872 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (50 hom.)
• Consequence: EMILIN2 NM_032048.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.45

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=0.002570331).
• BP6: Variant 18-2890855-C-A is Benign according to our data. Variant chr18-2890855-C-A is described in ClinVar as [Benign]. Clinvar id is 781351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0128 (1947/152284) while in subpopulation AFR AF= 0.0449 (1867/41560). AF 95% confidence interval is 0.0432. There are 41 homozygotes in gnomad4. There are 902 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EMILIN2	NM_032048.3	c.728C>A	p.Thr243Lys	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.728C>A	p.Thr243Lys	missense_variant	4/8	1	NM_032048.3	ENSP00000254528	P1
LPIN2	ENST00000697039.1	c.2547-5421G>T		intron_variant				ENSP00000513061

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1940 AN: 152166 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0449

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

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: 0.0000735

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00339 AC: 844 AN: 249292 Hom.: 25 AF XY: 0.00252 AC XY: 341 AN XY: 135156

Gnomad AFR exome AF: 0.0495

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000535

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00131 AC: 1913 AN: 1461588 Hom.: 50 Cov.: 31 AF XY: 0.00110 AC XY: 803 AN XY: 727056

Gnomad4 AFR exome AF: 0.0491

Gnomad4 AMR exome AF: 0.00177

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: 0.0000207

Gnomad4 OTH exome AF: 0.00257

GnomAD4 genome AF: 0.0128 AC: 1947 AN: 152284 Hom.: 41 Cov.: 32 AF XY: 0.0121 AC XY: 902 AN XY: 74450

Gnomad4 AFR AF: 0.0449

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00266 Hom.: 10

Bravo AF: 0.0147

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0452 AC: 199

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00414 AC: 503

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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	0.089
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Benign	0.87
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.79
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.97	D
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.067
Sift	Benign	0.064	T
Sift4G	Benign	0.10	T
Polyphen		0.41	B
Vest4		0.12
MVP		0.19
MPC		0.16
ClinPred		0.022	T
GERP RS		2.5
Varity_R		0.11
gMVP		0.27

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: rs36046935; hg19: chr18-2890853; COSMIC: COSV99039190;