rs2257019

Variant names:

• chr15-86587796-C-T
• rs2257019
• NM_001386094.1:c.2994+33259C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001386094.1(AGBL1):​c.2994+33259C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.954 in 152,288 control chromosomes in the GnomAD database, including 69,451 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.95 (69451 hom., cov: 33)
• Consequence: AGBL1 NM_001386094.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.373
• Publications: 2 publications found

Genes affected

AGBL1 (HGNC:26504): (AGBL carboxypeptidase 1) Polyglutamylation is a reversible posttranslational modification catalyzed by polyglutamylases that results in the addition of glutamate side chains on the modified protein. This gene encodes a glutamate decarboxylase that catalyzes the deglutamylation of polyglutamylated proteins. Mutations in this gene result in dominant late-onset Fuchs corneal dystrophy. [provided by RefSeq, Nov 2013]

AGBL1 Gene-Disease associations (from GenCC):

• Fuchs' endothelial dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• corneal dystrophy, Fuchs endothelial, 8

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGBL1	NM_001386094.1	c.2994+33259C>T		intron_variant	Intron 21 of 22	ENST00000614907.3	NP_001373023.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGBL1	ENST00000614907.3	c.2994+33259C>T		intron_variant	Intron 21 of 22	5	NM_001386094.1	ENSP00000490608.2
AGBL1	ENST00000441037.7	c.3057+31511C>T		intron_variant	Intron 22 of 24	5		ENSP00000413001.3
AGBL1	ENST00000681381.1	n.153+8960C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.954 AC: 145238 AN: 152170 Hom.: 69406 Cov.: 33

Gnomad AFR AF: 0.916

Gnomad AMI AF: 0.992

Gnomad AMR AF: 0.936

Gnomad ASJ AF: 0.980

Gnomad EAS AF: 0.988

Gnomad SAS AF: 0.945

Gnomad FIN AF: 0.935

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.981

Gnomad OTH AF: 0.966

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.954 AC: 145341 AN: 152288 Hom.: 69451 Cov.: 33 AF XY: 0.952 AC XY: 70918 AN XY: 74466

African (AFR) AF: 0.916 AC: 38051 AN: 41554

American (AMR) AF: 0.936 AC: 14302 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.980 AC: 3403 AN: 3472

East Asian (EAS) AF: 0.988 AC: 5110 AN: 5174

South Asian (SAS) AF: 0.945 AC: 4563 AN: 4830

European-Finnish (FIN) AF: 0.935 AC: 9924 AN: 10612

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.981 AC: 66746 AN: 68036

Other (OTH) AF: 0.966 AC: 2044 AN: 2116

Alfa AF: 0.955 Hom.: 42067

Bravo AF: 0.952

Asia WGS AF: 0.954 AC: 3316 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.61
DANN	Benign	0.55
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

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: rs2257019; hg19: chr15-87131027;