Genetic Variant NM_000292.3:c.3705A>C (chrX-18893488-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000292.3(PHKA2):c.3705A>C(p.Gln1235His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q1235Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 23)

Consequence

PHKA2
NM_000292.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.55

Publications

0 publications found

Variant links:

Genes affected

PHKA2 (HGNC:8926): (phosphorylase kinase regulatory subunit alpha 2) Phosphorylase kinase is a polymer of 16 subunits, four each of alpha, beta, gamma and delta. The alpha subunit includes the skeletal muscle and hepatic isoforms, and the hepatic isoform is encoded by this gene. The beta subunit is the same in both the muscle and hepatic isoforms, and encoded by one gene. The gamma subunit also includes the skeletal muscle and hepatic isoforms, which are encoded by two different genes. The delta subunit is a calmodulin and can be encoded by three different genes. The gamma subunits contain the active site of the enzyme, whereas the alpha and beta subunits have regulatory functions controlled by phosphorylation. The delta subunit mediates the dependence of the enzyme on calcium concentration. Mutations in this gene cause glycogen storage disease type 9A, also known as X-linked liver glycogenosis. Alternatively spliced transcript variants have been reported, but the full-length nature of these variants has not been determined.[provided by RefSeq, Feb 2010]

PHKA2 links:

PHKA2-AS1 (HGNC:44110): (PHKA2 antisense RNA 1)

PHKA2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000292.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PHKA2	NM_000292.3	MANE Select	c.3705A>C	p.Gln1235His	missense	Exon 33 of 33	NP_000283.1
PHKA2	NM_001440805.1		c.3729A>C	p.Gln1243His	missense	Exon 33 of 33	NP_001427734.1
PHKA2	NM_001440800.1		c.3651A>C	p.Gln1217His	missense	Exon 32 of 32	NP_001427729.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PHKA2	ENST00000379942.5	TSL:1 MANE Select	c.3705A>C	p.Gln1235His	missense	Exon 33 of 33	ENSP00000369274.4
PHKA2-AS1	ENST00000452900.5	TSL:1	n.467+150T>G		intron	N/A
PHKA2	ENST00000897868.1		c.3729A>C	p.Gln1243His	missense	Exon 33 of 33	ENSP00000567927.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

0.35

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.41

MetaRNN

Uncertain

0.72

MetaSVM

Uncertain

0.76

MutationAssessor

Uncertain

2.6

PhyloP100

-1.6

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.57

MutPred

0.38

Gain of catalytic residue at Q1235 (P = 0.0223)

MVP

0.90

MPC

0.33

ClinPred

0.99

GERP RS

-0.17

Varity_R

0.76

gMVP

0.49

Mutation Taster

=82/18

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over