Variant 1-109630697-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3PP5

The NM_001368809.2(AMPD2):c.2172G>C(p.Glu724Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E724Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

AMPD2
NM_001368809.2 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.800

Variant links:

Genes affected

AMPD2 (HGNC:469): (adenosine monophosphate deaminase 2) The protein encoded by this gene is important in purine metabolism by converting AMP to IMP. The encoded protein, which acts as a homotetramer, is one of three AMP deaminases found in mammals. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

AMPD2 links:

AMPD2 (HGNC:):

AMPD2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001368809.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-109630695-G-C is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), AMPD2. . Gene score misZ 2.8298 (greater than the threshold 3.09). Trascript score misZ 3.6281 (greater than threshold 3.09). GenCC has associacion of gene with pontocerebellar hypoplasia type 9, hereditary spastic paraplegia 63.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.797

PP5

Variant 1-109630697-G-C is Pathogenic according to our data. Variant chr1-109630697-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 132810.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMPD2	NM_001368809.2 linkuse as main transcript	c.2172G>C	p.Glu724Asp	missense_variant	18/19	ENST00000528667.7	NP_001355738.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMPD2	ENST00000528667.7 linkuse as main transcript	c.2172G>C	p.Glu724Asp	missense_variant	18/19	1	NM_001368809.2	ENSP00000436541.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia type 9

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

.;D;D;.;.;.

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

1.0

D;.;D;D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

4.0

.;H;H;.;.;.

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.5

N;D;D;N;N;N

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0020

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;.;D

Vest4

0.97

MutPred

0.52

.;Gain of phosphorylation at Y780 (P = 0.0912);Gain of phosphorylation at Y780 (P = 0.0912);.;.;.;

MVP

0.77

MPC

1.6

ClinPred

1.0

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.69

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over