9-132725722-C-T

Variant names:

• chr9-132725722-C-T
• rs200678908
• NM_152572.3:c.1406G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_152572.3(AK8):​c.1406G>A​(p.Gly469Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,582,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: AK8 NM_152572.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.07
• Publications: 2 publications found

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.16422924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK8	NM_152572.3	c.1406G>A	p.Gly469Glu	missense_variant	Exon 13 of 13	ENST00000298545.4	NP_689785.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AK8	ENST00000298545.4	c.1406G>A	p.Gly469Glu	missense_variant	Exon 13 of 13	1	NM_152572.3	ENSP00000298545.3
AK8	ENST00000467161.1	n.349G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
AK8	ENST00000476719.1	n.1843G>A		non_coding_transcript_exon_variant	Exon 12 of 12	5
AK8	ENST00000477396.5	n.2321G>A		non_coding_transcript_exon_variant	Exon 15 of 15	2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152124 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000120 AC: 25 AN: 209106 AF XY: 0.0000719

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.000654

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000140

Gnomad OTH exome AF: 0.000186

GnomAD4 exome AF: 0.000179 AC: 256 AN: 1430358 Hom.: 0 Cov.: 31 AF XY: 0.000185 AC XY: 131 AN XY: 707106

African (AFR) AF: 0.0000301 AC: 1 AN: 33248

American (AMR) AF: 0.000178 AC: 7 AN: 39388

Ashkenazi Jewish (ASJ) AF: 0.000314 AC: 8 AN: 25464

East Asian (EAS) AF: 0.00 AC: 0 AN: 38838

South Asian (SAS) AF: 0.00 AC: 0 AN: 81836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.000211 AC: 231 AN: 1094750

Other (OTH) AF: 0.000152 AC: 9 AN: 59300

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152124 Hom.: 0 Cov.: 31 AF XY: 0.0000942 AC XY: 7 AN XY: 74308

African (AFR) AF: 0.0000483 AC: 2 AN: 41422

American (AMR) AF: 0.000131 AC: 2 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000205 Hom.: 0

Bravo AF: 0.000147

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1406G>A (p.G469E) alteration is located in exon 13 (coding exon 13) of the AK8 gene. This alteration results from a G to A substitution at nucleotide position 1406, causing the glycine (G) at amino acid position 469 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	Uncertain	0.50
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.070	T
Eigen	Benign	0.0044
Eigen_PC	Benign	0.061
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.33
Sift	Benign	0.28	T
Sift4G	Benign	0.28	T
Polyphen		0.40	B
Vest4		0.47
MVP		0.66
MPC		0.59
ClinPred		0.15	T
GERP RS		5.1
Varity_R		0.19
gMVP		0.75
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs200678908; hg19: chr9-135601109; COSMIC: COSV53751304;