NM_024783.4:c.1046G>A

Variant names:

• chr11-47690661-C-T
• rs7941404
• NM_024783.4:c.1046G>A

Variant summary

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

The NM_024783.4(AGBL2):​c.1046G>A​(p.Arg349His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,613,956 control chromosomes in the GnomAD database, including 13,323 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R349C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.092 (857 hom., cov: 31)
  • Exomes 𝑓: 0.12 (12466 hom.)
• Consequence: AGBL2 NM_024783.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.370
• Publications: 28 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015272796).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGBL2	NM_024783.4	MANE Select	c.1046G>A	p.Arg349His	missense	Exon 10 of 19	NP_079059.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGBL2	ENST00000525123.6	TSL:1 MANE Select	c.1046G>A	p.Arg349His	missense	Exon 10 of 19	ENSP00000435582.1	Q5U5Z8-1
	AGBL2	ENST00000528244.5	TSL:2	c.932G>A	p.Arg311His	missense	Exon 9 of 16	ENSP00000436630.1	F6U0I4
	AGBL2	ENST00000532595.5	TSL:2	c.878G>A	p.Arg293His	missense	Exon 8 of 8	ENSP00000436063.1	E9PR59

Frequencies

GnomAD3 genomes AF: 0.0916 AC: 13929 AN: 151996 Hom.: 857 Cov.: 31

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.0815

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0330

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.106

GnomAD2 exomes AF: 0.0948 AC: 23827 AN: 251396 AF XY: 0.0960

Gnomad AFR exome AF: 0.0204

Gnomad AMR exome AF: 0.0604

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.123 AC: 180134 AN: 1461842 Hom.: 12466 Cov.: 32 AF XY: 0.121 AC XY: 88021 AN XY: 727232

African (AFR) AF: 0.0190 AC: 637 AN: 33480

American (AMR) AF: 0.0630 AC: 2819 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 3330 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.0379 AC: 3273 AN: 86254

European-Finnish (FIN) AF: 0.115 AC: 6162 AN: 53418

Middle Eastern (MID) AF: 0.0659 AC: 380 AN: 5768

European-Non Finnish (NFE) AF: 0.141 AC: 156904 AN: 1111968

Other (OTH) AF: 0.110 AC: 6621 AN: 60394

GnomAD4 genome AF: 0.0915 AC: 13926 AN: 152114 Hom.: 857 Cov.: 31 AF XY: 0.0877 AC XY: 6523 AN XY: 74362

African (AFR) AF: 0.0221 AC: 919 AN: 41526

American (AMR) AF: 0.0812 AC: 1239 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 459 AN: 3460

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0336 AC: 162 AN: 4818

European-Finnish (FIN) AF: 0.120 AC: 1266 AN: 10580

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.140 AC: 9506 AN: 67986

Other (OTH) AF: 0.105 AC: 221 AN: 2108

Alfa AF: 0.118 Hom.: 3102

Bravo AF: 0.0864

TwinsUK AF: 0.145 AC: 539

ALSPAC AF: 0.139 AC: 536

ESP6500AA AF: 0.0286 AC: 126

ESP6500EA AF: 0.139 AC: 1191

ExAC AF: 0.0943 AC: 11444

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.137

EpiControl AF: 0.138

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.32
DANN	Benign	0.16
DEOGEN2	Benign	0.00055	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0092	N
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.77	N
PhyloP100		-0.37
PrimateAI	Benign	0.20	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.016
Sift	Benign	1.0	T
Sift4G	Benign	0.70	T
Polyphen		0.0040	B
Vest4		0.020
MPC		0.13
ClinPred		0.0054	T
GERP RS		-0.36
Varity_R		0.021
gMVP		0.17
Mutation Taster		=99/1	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: rs7941404; hg19: chr11-47712213; COSMIC: COSV54092112; COSMIC: COSV54092112;