rs116807569

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_006412.4(AGPAT2):c.589-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000724 in 1,546,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

AGPAT2
NM_006412.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 2.08

Publications

12 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: Pathogenic. The variant received 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08721625 fraction of the gene. Cryptic splice site detected, with MaxEntScore 10, offset of -33, new splice context is: tgtgcctggcctgtccccAGggc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PP5

Variant 9-136674809-T-C is Pathogenic according to our data. Variant chr9-136674809-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 6625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006412.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGPAT2	NM_006412.4	MANE Select	c.589-2A>G		splice_acceptor intron	N/A	NP_006403.2
	AGPAT2	NM_001012727.2		c.493-2A>G		splice_acceptor intron	N/A	NP_001012745.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
AGPAT2	ENST00000371696.7	TSL:1 MANE Select	c.589-2A>G	splice_acceptor intron	N/A	ENSP00000360761.2
AGPAT2	ENST00000371694.7	TSL:1	c.493-2A>G	splice_acceptor intron	N/A	ENSP00000360759.3
AGPAT2	ENST00000472820.1	TSL:1	n.517-2A>G	splice_acceptor intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000407

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD2 exomes

AF:

0.000101

AC:

AN:

198966

AF XY:

0.0000645

show subpopulations

Gnomad AFR exome

AF:

0.00140

Gnomad AMR exome

AF:

0.0000787

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000359

AC:

AN:

1394460

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

690884

show subpopulations

African (AFR)

AF:

0.00145

AC:

AN:

30350

American (AMR)

AF:

0.0000550

AC:

AN:

36386

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23738

East Asian (EAS)

AF:

0.00

AC:

AN:

35236

South Asian (SAS)

AF:

0.00

AC:

AN:

76972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51016

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5484

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1077838

Other (OTH)

AF:

0.0000348

AC:

AN:

57440

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000407

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

41562

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000159

Hom.:

Bravo

AF:

0.000419

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital generalized lipodystrophy type 1 (5)

not provided (4)

Congenital generalized lipodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

PhyloP100

2.1

GERP RS

4.3

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.83

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.80

Position offset: 31

DS_AL_spliceai

1.0

Position offset: -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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over