rs73668354

Variant names:

• chr9-136677108-G-A
• rs73668354
• NM_006412.4:c.345C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136677108-G-A
• chr9-136677108-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006412.4(AGPAT2):​c.345C>T​(p.Cys115Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,613,124 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (45 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (50 hom.)
• Consequence: AGPAT2 NM_006412.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.156
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 9-136677108-G-A is Benign according to our data. Variant chr9-136677108-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.156 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1979/152298) while in subpopulation AFR AF = 0.0425 (1766/41554). AF 95% confidence interval is 0.0408. There are 45 homozygotes in GnomAd4. There are 948 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGPAT2	NM_006412.4	MANE Select	c.345C>T	p.Cys115Cys	synonymous	Exon 3 of 6	NP_006403.2
	AGPAT2	NM_001012727.2		c.345C>T	p.Cys115Cys	synonymous	Exon 3 of 5	NP_001012745.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGPAT2	ENST00000371696.7	TSL:1 MANE Select	c.345C>T	p.Cys115Cys	synonymous	Exon 3 of 6	ENSP00000360761.2
	AGPAT2	ENST00000371694.7	TSL:1	c.345C>T	p.Cys115Cys	synonymous	Exon 3 of 5	ENSP00000360759.3
	AGPAT2	ENST00000472820.1	TSL:1	n.273C>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1967 AN: 152180 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.0424

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00962

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00375 AC: 929 AN: 247990 AF XY: 0.00306

Gnomad AFR exome AF: 0.0439

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.000998

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000642

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00169 AC: 2464 AN: 1460826 Hom.: 50 Cov.: 37 AF XY: 0.00149 AC XY: 1081 AN XY: 726710

African (AFR) AF: 0.0482 AC: 1615 AN: 33480

American (AMR) AF: 0.00329 AC: 147 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52420

Middle Eastern (MID) AF: 0.00763 AC: 44 AN: 5768

European-Non Finnish (NFE) AF: 0.000313 AC: 348 AN: 1111968

Other (OTH) AF: 0.00446 AC: 269 AN: 60376

GnomAD4 genome AF: 0.0130 AC: 1979 AN: 152298 Hom.: 45 Cov.: 32 AF XY: 0.0127 AC XY: 948 AN XY: 74474

African (AFR) AF: 0.0425 AC: 1766 AN: 41554

American (AMR) AF: 0.00960 AC: 147 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68028

Other (OTH) AF: 0.0133 AC: 28 AN: 2108

Alfa AF: 0.0108 Hom.: 20

Bravo AF: 0.0147

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000830

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.29
DANN	Benign	0.94
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs73668354; hg19: chr9-139571560;