9-136677465-A-C

Variant names:

• chr9-136677465-A-C
• rs1554754454
• NM_006412.4:c.274T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006412.4(AGPAT2):​c.274T>G​(p.Cys92Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C92R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AGPAT2 NM_006412.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.12
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGPAT2	NM_006412.4	c.274T>G	p.Cys92Gly	missense_variant	Exon 2 of 6	ENST00000371696.7	NP_006403.2
AGPAT2	NM_001012727.2	c.274T>G	p.Cys92Gly	missense_variant	Exon 2 of 5		NP_001012745.1
AGPAT2	XM_047422636.1	c.-36T>G		5_prime_UTR_variant	Exon 2 of 6		XP_047278592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGPAT2	ENST00000371696.7	c.274T>G	p.Cys92Gly	missense_variant	Exon 2 of 6	1	NM_006412.4	ENSP00000360761.2
AGPAT2	ENST00000371694.7	c.274T>G	p.Cys92Gly	missense_variant	Exon 2 of 5	1		ENSP00000360759.3
AGPAT2	ENST00000470861.1	n.282T>G		non_coding_transcript_exon_variant	Exon 2 of 2	2
AGPAT2	ENST00000472820.1	n.-85T>G		upstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Benign	0.85
DEOGEN2	Uncertain	0.75	.;D;D
Eigen	Benign	0.063
Eigen_PC	Benign	0.054
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.74	T;.;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.9	L;L;L
PhyloP100		4.1
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-6.5	D;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.028	D;D;D
Sift4G	Benign	0.18	T;T;T
Polyphen		0.48	P;P;P
Vest4		0.58
MutPred		0.77		Gain of disorder (P = 0.0129);Gain of disorder (P = 0.0129);Gain of disorder (P = 0.0129);
MVP		0.94
MPC		0.40
ClinPred		0.91	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.64
gMVP		0.80
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs1554754454; hg19: chr9-139571917;