9-136687306-CCAGCAGCAG-CCAGCAGCAGCAG

Variant names:

• chr9-136687306-C-CCAG
• rs745429291
• NM_006412.4:c.49_51dupCTG

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_006412.4(AGPAT2):​c.49_51dupCTG​(p.Leu17dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0877 in 1,575,438 control chromosomes in the GnomAD database, including 5,825 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L17L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.069 (464 hom., cov: 32)
  • Exomes 𝑓: 0.090 (5361 hom.)
• Consequence: AGPAT2 NM_006412.4 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.28
• 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: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_006412.4
• BP6: Variant 9-136687306-C-CCAG is Benign according to our data. Variant chr9-136687306-C-CCAG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0965 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGPAT2	NM_006412.4	MANE Select	c.49_51dupCTG	p.Leu17dup	conservative_inframe_insertion	Exon 1 of 6	NP_006403.2
	AGPAT2	NM_001012727.2		c.49_51dupCTG	p.Leu17dup	conservative_inframe_insertion	Exon 1 of 5	NP_001012745.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGPAT2	ENST00000371696.7	TSL:1 MANE Select	c.49_51dupCTG	p.Leu17dup	conservative_inframe_insertion	Exon 1 of 6	ENSP00000360761.2
	AGPAT2	ENST00000371694.7	TSL:1	c.49_51dupCTG	p.Leu17dup	conservative_inframe_insertion	Exon 1 of 5	ENSP00000360759.3
	AGPAT2	ENST00000470861.1	TSL:2	n.57_59dupCTG		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10544 AN: 151760 Hom.: 461 Cov.: 32

Gnomad AFR AF: 0.0264

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0807

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.0386

Gnomad SAS AF: 0.0438

Gnomad FIN AF: 0.0467

Gnomad MID AF: 0.0924

Gnomad NFE AF: 0.0984

Gnomad OTH AF: 0.100

GnomAD2 exomes AF: 0.0731 AC: 13771 AN: 188298 AF XY: 0.0739

Gnomad AFR exome AF: 0.0236

Gnomad AMR exome AF: 0.0789

Gnomad ASJ exome AF: 0.0900

Gnomad EAS exome AF: 0.0346

Gnomad FIN exome AF: 0.0428

Gnomad NFE exome AF: 0.0936

Gnomad OTH exome AF: 0.0861

GnomAD4 exome AF: 0.0897 AC: 127686 AN: 1423566 Hom.: 5361 Cov.: 33 AF XY: 0.0887 AC XY: 62796 AN XY: 707946

African (AFR) AF: 0.0247 AC: 735 AN: 29740

American (AMR) AF: 0.0772 AC: 3214 AN: 41620

Ashkenazi Jewish (ASJ) AF: 0.0930 AC: 2327 AN: 25034

East Asian (EAS) AF: 0.0315 AC: 1117 AN: 35418

South Asian (SAS) AF: 0.0469 AC: 3887 AN: 82792

European-Finnish (FIN) AF: 0.0482 AC: 2240 AN: 46430

Middle Eastern (MID) AF: 0.0994 AC: 561 AN: 5646

European-Non Finnish (NFE) AF: 0.0987 AC: 108392 AN: 1098052

Other (OTH) AF: 0.0886 AC: 5213 AN: 58834

GnomAD4 genome AF: 0.0695 AC: 10548 AN: 151872 Hom.: 464 Cov.: 32 AF XY: 0.0660 AC XY: 4901 AN XY: 74220

African (AFR) AF: 0.0266 AC: 1104 AN: 41466

American (AMR) AF: 0.0807 AC: 1232 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 355 AN: 3460

East Asian (EAS) AF: 0.0383 AC: 197 AN: 5144

South Asian (SAS) AF: 0.0437 AC: 210 AN: 4810

European-Finnish (FIN) AF: 0.0467 AC: 494 AN: 10570

Middle Eastern (MID) AF: 0.0959 AC: 28 AN: 292

European-Non Finnish (NFE) AF: 0.0984 AC: 6678 AN: 67842

Other (OTH) AF: 0.0982 AC: 207 AN: 2108

Alfa AF: 0.0463 Hom.: 44

Asia WGS AF: 0.0490 AC: 169 AN: 3464

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Congenital generalized lipodystrophy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.3
Mutation Taster		=67/33	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs745429291; hg19: chr9-139581758; COSMIC: COSV65464649;