dbSNP rs933422777: AGPAT2:c.492+1G>C (chr9-136676960-C-G) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_006412.4(AGPAT2):c.492+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000447 in 1,341,282 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000045 ( 0 hom. )

Consequence

AGPAT2
NM_006412.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.30

Publications

0 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, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.7, offset of 23, new splice context is: tcgGTgggg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
AGPAT2	NM_006412.4 link	c.492+1G>C	splice_donor_variant, intron_variant	Intron 3 of 5	ENST00000371696.7	NP_006403.2
AGPAT2	NM_001012727.2 link	c.492+1G>C	splice_donor_variant, intron_variant	Intron 3 of 4		NP_001012745.1
AGPAT2	XM_047422636.1 link	c.183+1G>C	splice_donor_variant, intron_variant	Intron 3 of 5		XP_047278592.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
AGPAT2	ENST00000371696.7 link	c.492+1G>C	splice_donor_variant, intron_variant	Intron 3 of 5	1	NM_006412.4	ENSP00000360761.2
AGPAT2	ENST00000371694.7 link	c.492+1G>C	splice_donor_variant, intron_variant	Intron 3 of 4	1		ENSP00000360759.3
AGPAT2	ENST00000472820.1 link	n.420+1G>C	splice_donor_variant, intron_variant	Intron 1 of 3	1
AGPAT2	ENST00000470861.1 link	n.*67G>C	downstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000447

AC:

AN:

1341282

Hom.:

Cov.:

AF XY:

0.00000300

AC XY:

AN XY:

666060

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30148

American (AMR)

AF:

0.00

AC:

AN:

41050

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21892

East Asian (EAS)

AF:

0.00

AC:

AN:

30458

South Asian (SAS)

AF:

0.00

AC:

AN:

85092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5172

European-Non Finnish (NFE)

AF:

0.00000580

AC:

AN:

1035264

Other (OTH)

AF:

0.00

AC:

AN:

52660

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.567

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.93

PhyloP100

6.3

GERP RS

4.6

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.89

Position offset: 13

DS_DL_spliceai

1.0

Position offset: 1

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over