1-109630697-G-C

Variant names:

• chr1-109630697-G-C
• rs587777392
• NM_001368809.2:c.2172G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

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).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AMPD2 NM_001368809.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.800
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 9

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics
• hereditary spastic paraplegia 63

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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
• 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 VariationId is 132810.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001368809.2. 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
	AMPD2	NM_001368809.2	MANE Select	c.2172G>C	p.Glu724Asp	missense	Exon 18 of 19	NP_001355738.1
	AMPD2	NM_004037.9		c.2172G>C	p.Glu724Asp	missense	Exon 17 of 18	NP_004028.4
	AMPD2	NM_001308170.1		c.2109G>C	p.Glu703Asp	missense	Exon 16 of 17	NP_001295099.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMPD2	ENST00000528667.7	TSL:1 MANE Select	c.2172G>C	p.Glu724Asp	missense	Exon 18 of 19	ENSP00000436541.2
	AMPD2	ENST00000342115.8	TSL:1	c.2091G>C	p.Glu697Asp	missense	Exon 17 of 18	ENSP00000345498.4
	AMPD2	ENST00000526301.6	TSL:1	n.2235G>C		non_coding_transcript_exon	Exon 17 of 18

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pontocerebellar hypoplasia type 9 Pathogenic:1

Aug 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	4.0	H
PhyloP100		0.80
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.52		Gain of phosphorylation at Y780 (P = 0.0912)
MVP		0.77
MPC		1.6
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777392; hg19: chr1-110173319;