dbSNP rs370307434: AK8:p.Pro12Ala (chr9-132878222-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152572.3(AK8):c.34C>G(p.Pro12Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000823 in 1,458,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P12R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000061 ( 0 hom. )

Consequence

AK8
NM_152572.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.26

Publications

2 publications found

Variant links:

Genes affected

AK8 (HGNC:26526): (adenylate kinase 8) Enables AMP binding activity and nucleobase-containing compound kinase activity. Involved in nucleoside diphosphate phosphorylation and nucleoside triphosphate biosynthetic process. Located in 9+2 motile cilium. [provided by Alliance of Genome Resources, Apr 2022]

AK8 links:

SPACA9 (HGNC:1367): (sperm acrosome associated 9) Predicted to enable calcium-dependent protein binding activity. Located in cytoplasmic microtubule. [provided by Alliance of Genome Resources, Apr 2022]

SPACA9 links:

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ACMG classification

Classification was made for transcript

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=0.15928972).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152572.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AK8	NM_152572.3	MANE Select	c.34C>G	p.Pro12Ala	missense	Exon 1 of 13	NP_689785.1	Q96MA6-1
AK8	NM_001371772.1		c.34C>G	p.Pro12Ala	missense	Exon 1 of 11	NP_001358701.1
AK8	NM_001317959.2		c.-876C>G		5_prime_UTR	Exon 1 of 15	NP_001304888.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AK8	ENST00000298545.4	TSL:1 MANE Select	c.34C>G	p.Pro12Ala	missense	Exon 1 of 13	ENSP00000298545.3	Q96MA6-1
SPACA9	ENST00000372136.7	TSL:1	c.-252G>C		5_prime_UTR	Exon 1 of 4	ENSP00000361209.3	Q96E40-1
AK8	ENST00000885294.1		c.34C>G	p.Pro12Ala	missense	Exon 1 of 13	ENSP00000555353.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152168

Hom.:

Cov.:

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:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000286

AC:

AN:

139650

AF XY:

0.0000530

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:

0.0000579

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000612

AC:

AN:

1306286

Hom.:

Cov.:

AF XY:

0.00000784

AC XY:

AN XY:

637502

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26428

American (AMR)

AF:

0.00

AC:

AN:

24976

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18016

East Asian (EAS)

AF:

0.00

AC:

AN:

34418

South Asian (SAS)

AF:

0.00

AC:

AN:

61780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48194

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5022

European-Non Finnish (NFE)

AF:

0.00000677

AC:

AN:

1034112

Other (OTH)

AF:

0.0000187

AC:

AN:

53340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000263

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000347

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.24

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.64

M_CAP

Benign

0.068

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.0

PhyloP100

1.3

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.12

Sift

Benign

0.10

Sift4G

Benign

0.097

Polyphen

0.28

Vest4

0.12

MutPred

0.34

Loss of catalytic residue at P12 (P = 0.0295)

MVP

0.49

MPC

0.10

ClinPred

0.11

GERP RS

0.99

PromoterAI

0.032

Neutral

(source)

Varity_R

0.13

gMVP

0.33

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over