rs142248792

Positions:

chr9-136674756-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000371696.7(AGPAT2):c.640A>G(p.Lys214Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,517,790 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000079 ( 1 hom. )

Consequence

AGPAT2
ENST00000371696.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.842

Variant links:

Genes affected

AGPAT2 (HGNC:325): (1-acylglycerol-3-phosphate O-acyltransferase 2) This gene encodes a member of the 1-acylglycerol-3-phosphate O-acyltransferase family. The protein is located within the endoplasmic reticulum membrane and converts lysophosphatidic acid to phosphatidic acid, the second step in de novo phospholipid biosynthesis. Mutations in this gene have been associated with congenital generalized lipodystrophy (CGL), or Berardinelli-Seip syndrome, a disease characterized by a near absence of adipose tissue and severe insulin resistance. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

AGPAT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.007375121).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
AGPAT2	NM_006412.4 linkuse as main transcript	c.640A>G	p.Lys214Glu	missense_variant	5/6	ENST00000371696.7	NP_006403.2
AGPAT2	NM_001012727.2 linkuse as main transcript	c.544A>G	p.Lys182Glu	missense_variant	4/5		NP_001012745.1
AGPAT2	XM_047422636.1 linkuse as main transcript	c.331A>G	p.Lys111Glu	missense_variant	5/6		XP_047278592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGPAT2	ENST00000371696.7 linkuse as main transcript	c.640A>G	p.Lys214Glu	missense_variant	5/6	1	NM_006412.4	ENSP00000360761	P1	O15120-1
AGPAT2	ENST00000371694.7 linkuse as main transcript	c.544A>G	p.Lys182Glu	missense_variant	4/5	1		ENSP00000360759		O15120-2
AGPAT2	ENST00000472820.1 linkuse as main transcript	n.568A>G		non_coding_transcript_exon_variant	3/4	1

Frequencies

GnomAD3 genomes

AF:

0.000808

AC:

123

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000223

AC:

AN:

184054

Hom.:

AF XY:

0.000200

AC XY:

AN XY:

100062

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.000221

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000791

AC:

108

AN:

1365502

Hom.:

Cov.:

AF XY:

0.0000638

AC XY:

AN XY:

673854

show subpopulations

Gnomad4 AFR exome

AF:

0.00314

Gnomad4 AMR exome

AF:

0.000182

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000188

Gnomad4 OTH exome

AF:

0.000142

GnomAD4 genome

AF:

0.000808

AC:

123

AN:

152288

Hom.:

Cov.:

AF XY:

0.000739

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00289

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000179

Hom.:

Bravo

AF:

0.000910

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000207

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital generalized lipodystrophy type 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Apr 09, 2021	- -
Uncertain significance, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Potent mutations in AGPAT2 gene are associated with Congenital generalized lipodystrophy, type 1, which can present with insulin resistance, fatty liver and diabetes. However, the role of this particular variant rs142248792 in Congenital generalized lipodystrophy is yet to be ascertained. -

Monogenic diabetes

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Oct 16, 2015

ACMG Criteria: PP3, BP4 -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Uncertain

0.48

.;T;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.71

T;.;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.0074

T;T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

1.4

.;L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.3

N;N;N

REVEL

Benign

0.16

Sift

Benign

0.079

T;T;T

Sift4G

Benign

0.22

T;T;T

Polyphen

0.19

B;B;B

Vest4

0.23

MVP

0.83

MPC

0.23

ClinPred

0.014

GERP RS

1.9

Varity_R

0.11

gMVP

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over