Genetic Variant AK8:p.Asp341Glu (chr9-132792732-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152572.3(AK8):c.1023C>A(p.Asp341Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000385 in 1,558,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

AK8
NM_152572.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.00

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.049841225).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK8	NM_152572.3 link	c.1023C>A	p.Asp341Glu	missense_variant	Exon 11 of 13	ENST00000298545.4	NP_689785.1	Q96MA6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AK8	ENST00000298545.4 link	c.1023C>A	p.Asp341Glu	missense_variant	Exon 11 of 13	1	NM_152572.3	ENSP00000298545.3	Q96MA6-1
AK8	ENST00000476719.1 link	n.1460C>A		non_coding_transcript_exon_variant	Exon 10 of 12	5
AK8	ENST00000477396.5 link	n.1938C>A		non_coding_transcript_exon_variant	Exon 13 of 15	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152222

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:

0.00

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

GnomAD4 exome

AF:

0.00000284

AC:

AN:

1406068

Hom.:

Cov.:

AF XY:

0.00000288

AC XY:

AN XY:

694224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32034

American (AMR)

AF:

0.00

AC:

AN:

36698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25232

East Asian (EAS)

AF:

0.00

AC:

AN:

36456

South Asian (SAS)

AF:

0.00

AC:

AN:

79514

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4744

European-Non Finnish (NFE)

AF:

0.00000277

AC:

AN:

1083328

Other (OTH)

AF:

0.0000172

AC:

AN:

58202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1023C>A (p.D341E) alteration is located in exon 11 (coding exon 11) of the AK8 gene. This alteration results from a C to A substitution at nucleotide position 1023, causing the aspartic acid (D) at amino acid position 341 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.081

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.42

M_CAP

Benign

0.017

MetaRNN

Benign

0.050

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.78

PhyloP100

0.0

PrimateAI

Benign

0.30

PROVEAN

Benign

0.020

REVEL

Benign

0.024

Sift

Benign

0.69

Sift4G

Benign

0.74

Polyphen

0.0

Vest4

0.081

MutPred

0.33

Gain of loop (P = 0.2045);

MVP

0.32

MPC

0.095

ClinPred

0.026

GERP RS

0.081

Varity_R

0.042

gMVP

0.15

Mutation Taster

=100/0

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

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9-132792732-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over