9-132878252-C-G

Variant names:

• chr9-132878252-C-G
• rs377315557
• NM_152572.3:c.4G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152572.3(AK8):​c.4G>C​(p.Asp2His) 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. 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)
• Consequence: AK8 NM_152572.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.26
• Publications: 0 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]

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]

ACMG classification

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, 0.861

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK8	NM_152572.3	MANE Select	c.4G>C	p.Asp2His	missense	Exon 1 of 13	NP_689785.1	Q96MA6-1
	AK8	NM_001371772.1		c.4G>C	p.Asp2His	missense	Exon 1 of 11	NP_001358701.1
	AK8	NM_001317959.2		c.-906G>C		5_prime_UTR	Exon 1 of 15	NP_001304888.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK8	ENST00000298545.4	TSL:1 MANE Select	c.4G>C	p.Asp2His	missense	Exon 1 of 13	ENSP00000298545.3	Q96MA6-1
	SPACA9	ENST00000372136.7	TSL:1	c.-222C>G		5_prime_UTR	Exon 1 of 4	ENSP00000361209.3	Q96E40-1
	AK8	ENST00000885294.1		c.4G>C	p.Asp2His	missense	Exon 1 of 13	ENSP00000555353.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.25	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.51
MutPred		0.22		Loss of phosphorylation at T4 (P = 0.1664)
MVP		0.77
MPC		0.56
ClinPred		1.0	D
GERP RS		4.6
PromoterAI		-0.26	Neutral
Varity_R		0.84
gMVP		0.59
Mutation Taster		=277/23	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: rs377315557; hg19: chr9-135753639;