1-109621130-C-G

Variant names:

• chr1-109621130-C-G
• rs1650210949
• NM_001368809.2:c.-46C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001308170.1(AMPD2):​c.23C>G​(p.Ala8Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A8A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AMPD2 NM_001308170.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11
• Publications: 0 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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• hereditary spastic paraplegia 63

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20482478).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308170.1. 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
	AMPD2	NM_001368809.2	MANE Select	c.-46C>G		5_prime_UTR	Exon 2 of 19	NP_001355738.1	Q01433-1
	AMPD2	NM_001308170.1		c.23C>G	p.Ala8Gly	missense	Exon 1 of 17	NP_001295099.1	Q01433-4
	AMPD2	NM_139156.4		c.10+852C>G		intron	N/A	NP_631895.1	Q01433-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMPD2	ENST00000528667.7	TSL:1 MANE Select	c.-46C>G		5_prime_UTR	Exon 2 of 19	ENSP00000436541.2	Q01433-1
	AMPD2	ENST00000342115.8	TSL:1	c.10+852C>G		intron	N/A	ENSP00000345498.4	Q01433-2
	AMPD2	ENST00000369840.7	TSL:5	c.-46C>G		5_prime_UTR	Exon 1 of 18	ENSP00000358855.3	H0Y360

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446430 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 718658

African (AFR) AF: 0.00 AC: 0 AN: 32940

American (AMR) AF: 0.00 AC: 0 AN: 43564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25864

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38728

South Asian (SAS) AF: 0.00 AC: 0 AN: 84450

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5240

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104484

Other (OTH) AF: 0.00 AC: 0 AN: 59564

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 63;C4014354:Pontocerebellar hypoplasia type 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.77	T
PhyloP100		1.1
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.11	T
Polyphen		0.27	B
Vest4		0.33
MutPred		0.052		Loss of glycosylation at P7 (P = 0.1371)
MVP		0.50
ClinPred		0.35	T
GERP RS		3.9
PromoterAI		-0.079	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.091
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1650210949; hg19: chr1-110163752;