Genetic Variant AGBL2:p.Met671Ile (chr11-47679976-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_024783.4(AGBL2):c.2013G>A(p.Met671Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 29)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AGBL2
NM_024783.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.506

Publications

50 publications found

Variant links:

Genes affected

AGBL2 (HGNC:26296): (AGBL carboxypeptidase 2) Predicted to enable metallocarboxypeptidase activity. Predicted to be involved in protein side chain deglutamylation. Located in centriole and ciliary basal body. [provided by Alliance of Genome Resources, Apr 2022]

AGBL2 Gene-Disease associations (from GenCC):

epilepsy
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

AGBL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.058587223).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024783.4. 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
	AGBL2	NM_024783.4	MANE Select	c.2013G>A	p.Met671Ile	missense	Exon 13 of 19	NP_079059.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGBL2	ENST00000525123.6	TSL:1 MANE Select	c.2013G>A	p.Met671Ile	missense	Exon 13 of 19	ENSP00000435582.1
AGBL2	ENST00000528244.5	TSL:2	c.1899G>A	p.Met633Ile	missense	Exon 12 of 16	ENSP00000436630.1
AGBL2	ENST00000528609.5	TSL:1	n.*140G>A		non_coding_transcript_exon	Exon 3 of 9	ENSP00000431912.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151326

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.93e-7

AC:

AN:

1442046

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718764

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32882

American (AMR)

AF:

0.00

AC:

AN:

44266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25928

East Asian (EAS)

AF:

0.00

AC:

AN:

39532

South Asian (SAS)

AF:

0.00

AC:

AN:

85520

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53266

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

9.13e-7

AC:

AN:

1095338

Other (OTH)

AF:

0.00

AC:

AN:

59606

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

151326

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73828

African (AFR)

AF:

0.00

AC:

AN:

41154

American (AMR)

AF:

0.00

AC:

AN:

15150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10444

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67840

Other (OTH)

AF:

0.00

AC:

AN:

2084

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.0031

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.46

M_CAP

Benign

0.0022

MetaRNN

Benign

0.059

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PhyloP100

0.51

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.20

REVEL

Benign

0.026

Sift

Benign

0.079

Sift4G

Benign

0.16

Polyphen

0.0

Vest4

0.015

MutPred

0.19

Gain of methylation at K672 (P = 0.0258)

MVP

0.081

MPC

0.12

ClinPred

0.18

GERP RS

0.55

Varity_R

0.082

gMVP

0.50

Mutation Taster

=94/6

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over