Genetic Variant AK8:p.Asp2Tyr (chr9-132878252-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_152572.3(AK8):c.4G>T(p.Asp2Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000227 in 1,233,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

AK8
NM_152572.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.26

Publications

1 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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.873

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.4G>T	p.Asp2Tyr	missense	Exon 1 of 13	NP_689785.1	Q96MA6-1
AK8	NM_001371772.1		c.4G>T	p.Asp2Tyr	missense	Exon 1 of 11	NP_001358701.1
AK8	NM_001317959.2		c.-906G>T		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.4G>T	p.Asp2Tyr	missense	Exon 1 of 13	ENSP00000298545.3	Q96MA6-1
SPACA9	ENST00000372136.7	TSL:1	c.-222C>A		5_prime_UTR	Exon 1 of 4	ENSP00000361209.3	Q96E40-1
AK8	ENST00000885294.1		c.4G>T	p.Asp2Tyr	missense	Exon 1 of 13	ENSP00000555353.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000839

AC:

AN:

119154

AF XY:

0.00

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:

0.0000227

AC:

AN:

1233500

Hom.:

Cov.:

AF XY:

0.0000184

AC XY:

AN XY:

598194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25228

American (AMR)

AF:

0.00

AC:

AN:

20544

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16546

East Asian (EAS)

AF:

0.00

AC:

AN:

31718

South Asian (SAS)

AF:

0.0000212

AC:

AN:

47160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44654

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4574

European-Non Finnish (NFE)

AF:

0.0000272

AC:

AN:

993578

Other (OTH)

AF:

0.00

AC:

AN:

49498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000177

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.26

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.87

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.7

PhyloP100

3.3

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.57

MutPred

0.39

Gain of catalytic residue at D2 (P = 0.0031)

MVP

0.68

MPC

0.57

ClinPred

0.99

GERP RS

4.6

PromoterAI

-0.12

Neutral

(source)

Varity_R

0.84

gMVP

0.67

Mutation Taster

=277/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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