dbSNP rs1057517655: AGPAT2:p.Gln226* (chr9-136673913-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_006412.4(AGPAT2):c.676C>T(p.Gln226*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. Q226Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AGPAT2
NM_006412.4 stop_gained

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 1.94

Publications

4 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: Likely_pathogenic. The variant received 6 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.192 CDS is truncated, and there are 3 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
AGPAT2	NM_006412.4 link	c.676C>T	p.Gln226*	stop_gained	Exon 6 of 6	ENST00000371696.7	NP_006403.2
AGPAT2	NM_001012727.2 link	c.580C>T	p.Gln194*	stop_gained	Exon 5 of 5		NP_001012745.1
AGPAT2	XM_047422636.1 link	c.367C>T	p.Gln123*	stop_gained	Exon 6 of 6		XP_047278592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
AGPAT2	ENST00000371696.7 link	c.676C>T	p.Gln226*	stop_gained	Exon 6 of 6	1	NM_006412.4	ENSP00000360761.2
AGPAT2	ENST00000371694.7 link	c.580C>T	p.Gln194*	stop_gained	Exon 5 of 5	1		ENSP00000360759.3
AGPAT2	ENST00000472820.1 link	n.604C>T		non_coding_transcript_exon_variant	Exon 4 of 4	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1429748

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

708314

African (AFR)

AF:

0.00

AC:

AN:

32794

American (AMR)

AF:

0.00

AC:

AN:

41956

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25040

East Asian (EAS)

AF:

0.00

AC:

AN:

38258

South Asian (SAS)

AF:

0.00

AC:

AN:

81660

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51058

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4256

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1095766

Other (OTH)

AF:

0.00

AC:

AN:

58960

GnomAD4 genome

Cov.:

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

Congenital generalized lipodystrophy type 1

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.95

PhyloP100

1.9

Vest4

0.29

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=4/196

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over