rs142993240

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006412.4(AGPAT2):c.475C>T(p.Arg159Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00516 in 1,570,472 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R159L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0045 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0052 ( 30 hom. )

Consequence

AGPAT2
NM_006412.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:9O:1

Conservation

PhyloP100: 2.85

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

congenital generalized lipodystrophy type 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Berardinelli-Seip congenital lipodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
neonatal diabetes mellitus
Inheritance: AR Classification: LIMITED Submitted by: Genomics England PanelApp

AGPAT2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013234198).

BP6

Variant 9-136676978-G-A is Benign according to our data. Variant chr9-136676978-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00451 (671/148876) while in subpopulation SAS AF = 0.00814 (37/4548). AF 95% confidence interval is 0.00607. There are 6 homozygotes in GnomAd4. There are 327 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
AGPAT2	NM_006412.4 link	c.475C>T	p.Arg159Cys	missense_variant	Exon 3 of 6	ENST00000371696.7	NP_006403.2
AGPAT2	NM_001012727.2 link	c.475C>T	p.Arg159Cys	missense_variant	Exon 3 of 5		NP_001012745.1
AGPAT2	XM_047422636.1 link	c.166C>T	p.Arg56Cys	missense_variant	Exon 3 of 6		XP_047278592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
AGPAT2	ENST00000371696.7 link	c.475C>T	p.Arg159Cys	missense_variant	Exon 3 of 6	1	NM_006412.4	ENSP00000360761.2
AGPAT2	ENST00000371694.7 link	c.475C>T	p.Arg159Cys	missense_variant	Exon 3 of 5	1		ENSP00000360759.3
AGPAT2	ENST00000472820.1 link	n.403C>T		non_coding_transcript_exon_variant	Exon 1 of 4	1
AGPAT2	ENST00000470861.1 link	n.*49C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00451

AC:

671

AN:

148742

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00141

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00568

Gnomad ASJ

AF:

0.0102

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00814

Gnomad FIN

AF:

0.00142

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.00621

Gnomad OTH

AF:

0.00824

GnomAD2 exomes

AF:

0.00514

AC:

1277

AN:

248240

AF XY:

0.00561

show subpopulations

Gnomad AFR exome

AF:

0.000557

Gnomad AMR exome

AF:

0.00498

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.00624

Gnomad OTH exome

AF:

0.00918

GnomAD4 exome

AF:

0.00523

AC:

7438

AN:

1421596

Hom.:

Cov.:

AF XY:

0.00541

AC XY:

3823

AN XY:

706970

show subpopulations

African (AFR)

AF:

0.000897

AC:

AN:

32320

American (AMR)

AF:

0.00525

AC:

228

AN:

43418

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

278

AN:

24514

East Asian (EAS)

AF:

0.00

AC:

AN:

36672

South Asian (SAS)

AF:

0.00745

AC:

640

AN:

85894

European-Finnish (FIN)

AF:

0.00207

AC:

102

AN:

49284

Middle Eastern (MID)

AF:

0.0200

AC:

111

AN:

5554

European-Non Finnish (NFE)

AF:

0.00524

AC:

5691

AN:

1086356

Other (OTH)

AF:

0.00623

AC:

359

AN:

57584

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

433

867

1300

1734

2167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00451

AC:

671

AN:

148876

Hom.:

Cov.:

AF XY:

0.00450

AC XY:

327

AN XY:

72600

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

40594

American (AMR)

AF:

0.00567

AC:

AN:

14980

Ashkenazi Jewish (ASJ)

AF:

0.0102

AC:

AN:

3438

East Asian (EAS)

AF:

0.00

AC:

AN:

4856

South Asian (SAS)

AF:

0.00814

AC:

AN:

4548

European-Finnish (FIN)

AF:

0.00142

AC:

AN:

9860

Middle Eastern (MID)

AF:

0.0274

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00621

AC:

418

AN:

67330

Other (OTH)

AF:

0.00815

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

126

157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00599

Hom.:

Bravo

AF:

0.00459

TwinsUK

AF:

0.00485

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00558

AC:

ExAC

AF:

0.00545

AC:

661

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Dec 30, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AGPAT2: BS2

Dec 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:3

Aug 18, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 07, 2018

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 19, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: AGPAT2 c.475C>T (p.Arg159Cys) results in a non-conservative amino acid change located in the Phospholipid/glycerol acyltransferase domain (IPR002123) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0051 in 248240 control chromosomes in the gnomAD database, including 9 homozygotes. The observed variant frequency is approximately 5.9 fold of the estimated maximal expected allele frequency for a pathogenic variant in AGPAT2 causing Congenital Generalized Lipodystrophy phenotype (0.00087), strongly suggesting that the variant is benign. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.

Congenital generalized lipodystrophy type 1

Benign:1Other:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain risk allele

Review Status:flagged submission

Collection Method:research

Potent mutations in AGPAT2 gene are associated with Congenital generalized lipodystrophy, type 1, which can present with insulin resistance, fatty liver and diabetes. rs142993240 variant is prevalent with Congenital Generalized Lipoatrophy. However, the role of this rs142993240 particular variant is yet to be ascertained.

AGPAT2-related disorder

Benign:1

May 01, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Monogenic diabetes

Benign:1

Feb 22, 2019

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

ACMG criteria: BS1 (1% in gnomAD AJ population, 0.5% overall MAF in gnomAD; disease prevalence 1:10 million gives MAF of 0.03%), BS2 (8 homozygotes in gnomAD) [REVEL 0.582, BP4 (3 predictors), PP3 (6 predictors)= conflicting evidence, not using]; heterozygotes mutation found in brother and sister with lipodytrophy phenotype Simsir et al. 2015 ""Heterozygous AGPAT2 Mutation, Diabetes, and Lipodystrophy in Extremities"" (no PMID)= benign

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;D;D

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.28

LIST_S2

Benign

0.84

T;.;T

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Uncertain

0.56

MutationAssessor

Benign

1.9

L;L;L

PhyloP100

2.9

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.3

N;N;N

Sift

Benign

0.040

D;T;T

Sift4G

Benign

0.13

T;T;T

Vest4

0.33

ClinPred

0.015

GERP RS

2.7

Varity_R

0.28

gMVP

0.55

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over