rs116807569
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_006412.4(AGPAT2):c.589-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000724 in 1,546,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_006412.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AGPAT2 | NM_006412.4 | c.589-2A>G | splice_acceptor_variant, intron_variant | Intron 4 of 5 | ENST00000371696.7 | NP_006403.2 | ||
AGPAT2 | NM_001012727.2 | c.493-2A>G | splice_acceptor_variant, intron_variant | Intron 3 of 4 | NP_001012745.1 | |||
AGPAT2 | XM_047422636.1 | c.280-2A>G | splice_acceptor_variant, intron_variant | Intron 4 of 5 | XP_047278592.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AGPAT2 | ENST00000371696.7 | c.589-2A>G | splice_acceptor_variant, intron_variant | Intron 4 of 5 | 1 | NM_006412.4 | ENSP00000360761.2 | |||
AGPAT2 | ENST00000371694.7 | c.493-2A>G | splice_acceptor_variant, intron_variant | Intron 3 of 4 | 1 | ENSP00000360759.3 | ||||
AGPAT2 | ENST00000472820.1 | n.517-2A>G | splice_acceptor_variant, intron_variant | Intron 2 of 3 | 1 |
Frequencies
GnomAD3 genomes AF: 0.000407 AC: 62AN: 152164Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000101 AC: 20AN: 198966Hom.: 0 AF XY: 0.0000645 AC XY: 7AN XY: 108540
GnomAD4 exome AF: 0.0000359 AC: 50AN: 1394460Hom.: 0 Cov.: 30 AF XY: 0.0000304 AC XY: 21AN XY: 690884
GnomAD4 genome AF: 0.000407 AC: 62AN: 152282Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30AN XY: 74480
ClinVar
Submissions by phenotype
Congenital generalized lipodystrophy type 1 Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 06, 2024 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 06, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 03, 2023 | The AGPAT2 c.589-2A>G variant, also referred to as IVS4-2A>G, results a substitution within the consensus splice acceptor site. This variant is predicted to result in a frameshift and premature termination with addition of novel amino acids (PMID: 11967537; 12765973). The c.589-2A>G variant has been reported in at least 24 unrelated individuals in a homozygous state and at least 11 unrelated individuals in either a confirmed or presumed compound heterozygous state with phenotypes consistent with congenital generalized lipodystrophy (PMID: 11967537; 12765973; 14557463; 31416577; 32280377; 34318892). This variant segregated with disease in multiple families (PMID: 11967537; 12765973 14557463). The c.589-2A>G variant is reported at a frequency of 0.001496 in the African/African American population of the Genome Aggregation Database (version 3.1.2). Based on the available evidence, the c.589-2A>G variant is classified as pathogenic for congenital generalized lipodystrophy. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2004 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 28, 2024 | This sequence change affects an acceptor splice site in intron 4 of the AGPAT2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AGPAT2 are known to be pathogenic (PMID: 11967537, 15181077). This variant is present in population databases (rs116807569, gnomAD 0.2%). Disruption of this splice site has been observed in individual(s) with congenital generalized lipodystrophy (PMID: 11967537, 32876150). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6625). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 13, 2022 | Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30266686, 11967537, 25525159, 19278620, 26072926, 22344438, 15181077, 32041611, 12765973, 32280377, SchweisbergerC2021[Abstract], 34033296, 31416577, 30296183, 30595509, 34318892) - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Congenital generalized lipodystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 13, 2023 | Variant summary: AGPAT2 c.589-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. The variant allele was found at a frequency of 0.0001 in 198966 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in AGPAT2 causing Congenital Generalized Lipodystrophy (0.0001 vs 0.00087), allowing no conclusion about variant significance. c.589-2A>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Congenital Generalized Lipodystrophy (examples: Agarwal_2002 and Magre_2003). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11967537, 12765973). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at