rs142248792

chr9-136674756-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006412.4(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 NM_006412.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.842

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]

ACMG classification

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	UniProt
AGPAT2	NM_006412.4	c.640A>G	p.Lys214Glu	missense_variant	5/6	ENST00000371696.7
AGPAT2	NM_001012727.2	c.544A>G	p.Lys182Glu	missense_variant	4/5
AGPAT2	XM_047422636.1	c.331A>G	p.Lys111Glu	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGPAT2	ENST00000371696.7	c.640A>G	p.Lys214Glu	missense_variant	5/6	1	NM_006412.4	P1
AGPAT2	ENST00000371694.7	c.544A>G	p.Lys182Glu	missense_variant	4/5	1
AGPAT2	ENST00000472820.1	n.568A>G		non_coding_transcript_exon_variant	3/4	1

Frequencies

GnomAD3 genomes AF: 0.000808 AC: 123 AN: 152170 Hom.: 0 Cov.: 33

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: 41 AN: 184054 Hom.: 0 AF XY: 0.000200 AC XY: 20 AN XY: 100062

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.: 1 Cov.: 30 AF XY: 0.0000638 AC XY: 43 AN XY: 673854

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.: 0 Cov.: 33 AF XY: 0.000739 AC XY: 55 AN XY: 74458

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.: 0

Bravo AF: 0.000910

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000207 AC: 25

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital generalized lipodystrophy type 1 Uncertain:2

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Apr 09, 2021	- -

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

Invitae

Feb 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	10
Dann	Benign	0.89
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.71	T;.;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.0074	T;T;T
MetaSVM	Uncertain	-0.15	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
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	T
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

Other links and lift over

dbSNP: rs142248792; hg19: chr9-139569208;