X-18893488-T-C

Variant names:

• chrX-18893488-T-C
• rs112249974
• NM_000292.3:c.3705A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001440805.1(PHKA2):​c.3729A>G​(p.Gln1243Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000765 in 1,208,857 control chromosomes in the GnomAD database, including 1 homozygotes. There are 247 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (0 hom., 111 hem., cov: 23)
  • Exomes 𝑓: 0.00046 (1 hom. 136 hem.)
• Consequence: PHKA2 NM_001440805.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.55
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant X-18893488-T-C is Benign according to our data. Variant chrX-18893488-T-C is described in ClinVar as Benign. ClinVar VariationId is 255777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.55 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00379 (423/111704) while in subpopulation AFR AF = 0.013 (401/30747). AF 95% confidence interval is 0.012. There are 0 homozygotes in GnomAd4. There are 111 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 111 XL,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440805.1. 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.3705A>G	p.Gln1235Gln	synonymous	Exon 33 of 33	NP_000283.1
	PHKA2	NM_001440805.1		c.3729A>G	p.Gln1243Gln	synonymous	Exon 33 of 33	NP_001427734.1
	PHKA2	NM_001440800.1		c.3651A>G	p.Gln1217Gln	synonymous	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.3705A>G	p.Gln1235Gln	synonymous	Exon 33 of 33	ENSP00000369274.4
	PHKA2-AS1	ENST00000452900.5	TSL:1	n.467+150T>C		intron	N/A
	PHKA2	ENST00000897868.1		c.3729A>G	p.Gln1243Gln	synonymous	Exon 33 of 33	ENSP00000567927.1

Frequencies

GnomAD3 genomes AF: 0.00378 AC: 422 AN: 111650 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00152

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00267

GnomAD2 exomes AF: 0.00107 AC: 197 AN: 183506 AF XY: 0.000707

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000366

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000458 AC: 502 AN: 1097153 Hom.: 1 Cov.: 29 AF XY: 0.000375 AC XY: 136 AN XY: 362529

African (AFR) AF: 0.0151 AC: 398 AN: 26379

American (AMR) AF: 0.000937 AC: 33 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54121

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40510

Middle Eastern (MID) AF: 0.000726 AC: 3 AN: 4132

European-Non Finnish (NFE) AF: 0.0000238 AC: 20 AN: 841161

Other (OTH) AF: 0.000999 AC: 46 AN: 46060

GnomAD4 genome AF: 0.00379 AC: 423 AN: 111704 Hom.: 0 Cov.: 23 AF XY: 0.00328 AC XY: 111 AN XY: 33886

African (AFR) AF: 0.0130 AC: 401 AN: 30747

American (AMR) AF: 0.00152 AC: 16 AN: 10547

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3555

South Asian (SAS) AF: 0.00 AC: 0 AN: 2614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6081

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53103

Other (OTH) AF: 0.00264 AC: 4 AN: 1515

Alfa AF: 0.000515 Hom.: 3

Bravo AF: 0.00447

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Glycogen storage disease IXa1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.036
DANN	Benign	0.75
PhyloP100		-1.6
Mutation Taster		=99/1	polymorphism (auto)

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: rs112249974; hg19: chrX-18911606;