9-132823252-T-C

Position:

• chr9-132823252-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_152572.3(AK8):​c.842A>G​(p.Lys281Arg) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AK8 NM_152572.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.12

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AK8	NM_152572.3	c.842A>G	p.Lys281Arg	missense_variant	9/13	ENST00000298545.4	NP_689785.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AK8	ENST00000298545.4	c.842A>G	p.Lys281Arg	missense_variant	9/13	1	NM_152572.3	ENSP00000298545.3
AK8	ENST00000476719.1	n.1279A>G		non_coding_transcript_exon_variant	8/12	5
AK8	ENST00000477396.5	n.1757A>G		non_coding_transcript_exon_variant	11/15	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

The c.842A>G (p.K281R) alteration is located in exon 9 (coding exon 9) of the AK8 gene. This alteration results from a A to G substitution at nucleotide position 842, causing the lysine (K) at amino acid position 281 to be replaced by an arginine (R). 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	0.12
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.59
Sift	Benign	0.099	T
Sift4G	Benign	0.17	T
Polyphen		0.84	P
Vest4		0.50
MutPred		0.90		Loss of ubiquitination at K281 (P = 0.0192);
MVP		0.80
MPC		0.33
ClinPred		0.79	D
GERP RS		5.6
Varity_R		0.16
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs1841728248; hg19: chr9-135698639;