14-67642210-A-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001172.4(ARG2):​c.209A>G​(p.Asp70Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000775 in 1,613,820 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000077 ( 3 hom. )

Consequence

ARG2
NM_001172.4 missense

Scores

6
8
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

Publications

0 publications found
Variant links:
Genes affected
ARG2 (HGNC:664): (arginase 2) Arginase catalyzes the hydrolysis of arginine to ornithine and urea. At least two isoforms of mammalian arginase exists (types I and II) which differ in their tissue distribution, subcellular localization, immunologic crossreactivity and physiologic function. The type II isoform encoded by this gene, is located in the mitochondria and expressed in extra-hepatic tissues, especially kidney. The physiologic role of this isoform is poorly understood; it is thought to play a role in nitric oxide and polyamine metabolism. Transcript variants of the type II gene resulting from the use of alternative polyadenylation sites have been described. [provided by RefSeq, Jul 2008]
GPHN (HGNC:15465): (gephyrin) This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperplexia and also lead to molybdenum cofactor deficiency. Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known. [provided by RefSeq, Jul 2008]
GPHN Gene-Disease associations (from GenCC):
  • sulfite oxidase deficiency due to molybdenum cofactor deficiency type C
    Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
  • hereditary hyperekplexia
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • complex neurodevelopmental disorder
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARG2NM_001172.4 linkc.209A>G p.Asp70Gly missense_variant Exon 3 of 8 ENST00000261783.4 NP_001163.1 P78540A0A024R6A0
GPHNXM_047430879.1 linkc.1313-92985A>G intron_variant Intron 14 of 14 XP_047286835.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ARG2ENST00000261783.4 linkc.209A>G p.Asp70Gly missense_variant Exon 3 of 8 1 NM_001172.4 ENSP00000261783.3 P78540
ARG2ENST00000556491.1 linkn.207A>G non_coding_transcript_exon_variant Exon 3 of 4 5
ARG2ENST00000557120.5 linkn.251A>G non_coding_transcript_exon_variant Exon 3 of 5 2

Frequencies

GnomAD3 genomes
AF:
0.0000855
AC:
13
AN:
152080
Hom.:
0
Cov.:
32
show subpopulations
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:
0.00249
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000119
AC:
30
AN:
251228
AF XY:
0.000192
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000766
AC:
112
AN:
1461740
Hom.:
3
Cov.:
30
AF XY:
0.000120
AC XY:
87
AN XY:
727158
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33474
American (AMR)
AF:
0.00
AC:
0
AN:
44702
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39694
South Asian (SAS)
AF:
0.00129
AC:
111
AN:
86236
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111920
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
6
13
19
26
32
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000855
AC:
13
AN:
152080
Hom.:
0
Cov.:
32
AF XY:
0.000175
AC XY:
13
AN XY:
74274
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41402
American (AMR)
AF:
0.00
AC:
0
AN:
15260
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.00249
AC:
12
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68016
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000688
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000988
AC:
12

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 16, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.209A>G (p.D70G) alteration is located in exon 3 (coding exon 3) of the ARG2 gene. This alteration results from a A to G substitution at nucleotide position 209, causing the aspartic acid (D) at amino acid position 70 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.72
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.17
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
D
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.90
D
M_CAP
Benign
0.047
D
MetaRNN
Uncertain
0.55
D
MetaSVM
Uncertain
-0.20
T
MutationAssessor
Pathogenic
3.4
M
PhyloP100
9.3
PrimateAI
Uncertain
0.59
T
PROVEAN
Pathogenic
-4.8
D
REVEL
Uncertain
0.39
Sift
Uncertain
0.0040
D
Sift4G
Benign
0.068
T
Polyphen
1.0
D
Vest4
0.89
MutPred
0.56
Gain of catalytic residue at K66 (P = 5e-04);
MVP
0.56
MPC
0.77
ClinPred
0.91
D
GERP RS
4.3
Varity_R
0.89
gMVP
0.83
Mutation Taster
=32/68
disease causing

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

Other links and lift over

dbSNP: rs765220457; hg19: chr14-68108927; API