chrX-18893528-T-G

Variant names:

• chrX-18893528-T-G
• rs559164945
• NM_000292.3:c.3665A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000292.3(PHKA2):​c.3665A>C​(p.Tyr1222Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000024 in 1,210,039 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000023 (0 hom. 13 hem.)
• Consequence: PHKA2 NM_000292.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.81
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05097395).
• BP6: Variant X-18893528-T-G is Benign according to our data. Variant chrX-18893528-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2707197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000357 (4/112057) while in subpopulation EAS AF = 0.000841 (3/3567). AF 95% confidence interval is 0.000228. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 13 XL,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKA2	NM_000292.3	MANE Select	c.3665A>C	p.Tyr1222Ser	missense	Exon 33 of 33	NP_000283.1	P46019
	PHKA2	NM_001440805.1		c.3689A>C	p.Tyr1230Ser	missense	Exon 33 of 33	NP_001427734.1
	PHKA2	NM_001440800.1		c.3611A>C	p.Tyr1204Ser	missense	Exon 32 of 32	NP_001427729.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKA2	ENST00000379942.5	TSL:1 MANE Select	c.3665A>C	p.Tyr1222Ser	missense	Exon 33 of 33	ENSP00000369274.4	P46019
	PHKA2-AS1	ENST00000452900.5	TSL:1	n.467+190T>G		intron	N/A
	PHKA2	ENST00000897868.1		c.3689A>C	p.Tyr1230Ser	missense	Exon 33 of 33	ENSP00000567927.1

Frequencies

GnomAD3 genomes AF: 0.0000446 AC: 5 AN: 112004 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00112

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000708 AC: 13 AN: 183500 AF XY: 0.0000883

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000794

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000228 AC: 25 AN: 1097982 Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 13 AN XY: 363336

African (AFR) AF: 0.0000379 AC: 1 AN: 26399

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.000331 AC: 10 AN: 30205

South Asian (SAS) AF: 0.000166 AC: 9 AN: 54141

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841908

Other (OTH) AF: 0.000108 AC: 5 AN: 46087

GnomAD4 genome AF: 0.0000357 AC: 4 AN: 112057 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34237

African (AFR) AF: 0.0000324 AC: 1 AN: 30850

American (AMR) AF: 0.00 AC: 0 AN: 10620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.000841 AC: 3 AN: 3567

South Asian (SAS) AF: 0.00 AC: 0 AN: 2652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53159

Other (OTH) AF: 0.00 AC: 0 AN: 1529

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000576 AC: 7

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Glycogen storage disease IXa1 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Uncertain	0.51	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.051	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.8
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.34
Sift	Benign	0.18	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.21
MutPred		0.64		Gain of disorder (P = 0.0093)
MVP		0.69
MPC		0.31
ClinPred		0.073	T
GERP RS		5.9
Varity_R		0.37
gMVP		0.60
Mutation Taster		=96/4	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: rs559164945; hg19: chrX-18911646;