NM_002637.4:c.2462G>A

Variant names:

• chrX-72611092-C-T
• rs139803629
• NM_002637.4:c.2462G>A

Variant summary

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

The NM_002637.4(PHKA1):​c.2462G>A​(p.Arg821His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00444 in 1,203,695 control chromosomes in the GnomAD database, including 12 homozygotes. There are 1,647 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R821C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., 70 hem., cov: 22)
  • Exomes 𝑓: 0.0046 (10 hom. 1577 hem.)
• Consequence: PHKA1 NM_002637.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.96
• Publications: 4 publications found

Genes affected

PHKA1 (HGNC:8925): (phosphorylase kinase regulatory subunit alpha 1) 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 skeletal muscle 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 9D, also known as X-linked muscle glycogenosis. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene. A pseudogene has been found on chromosome 1.[provided by RefSeq, Feb 2010]

PHKA1 Gene-Disease associations (from GenCC):

• glycogen storage disease IXd

  Inheritance: XL, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.009200335).
• BP6: Variant X-72611092-C-T is Benign according to our data. Variant chrX-72611092-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00274 (305/111410) while in subpopulation NFE AF = 0.00496 (263/53061). AF 95% confidence interval is 0.00446. There are 2 homozygotes in GnomAd4. There are 70 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 XL,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002637.4. 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
	PHKA1	NM_002637.4	MANE Select	c.2462G>A	p.Arg821His	missense	Exon 22 of 32	NP_002628.2	P46020-1
	PHKA1	NM_001431068.1		c.2462G>A	p.Arg821His	missense	Exon 22 of 33	NP_001417997.1	A6NMN0
	PHKA1	NM_001122670.2		c.2462G>A	p.Arg821His	missense	Exon 22 of 31	NP_001116142.1	P46020-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKA1	ENST00000373542.9	TSL:1 MANE Select	c.2462G>A	p.Arg821His	missense	Exon 22 of 32	ENSP00000362643.4	P46020-1
	PHKA1	ENST00000339490.7	TSL:1	c.2462G>A	p.Arg821His	missense	Exon 22 of 31	ENSP00000342469.3	P46020-2
	PHKA1	ENST00000541944.5	TSL:1	c.2285G>A	p.Arg762His	missense	Exon 21 of 30	ENSP00000441251.1	P46020-3

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 305 AN: 111357 Hom.: 2 Cov.: 22

Gnomad AFR AF: 0.000783

Gnomad AMI AF: 0.00876

Gnomad AMR AF: 0.000768

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000167

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00496

Gnomad OTH AF: 0.00201

GnomAD2 exomes AF: 0.00331 AC: 605 AN: 182660 AF XY: 0.00316

Gnomad AFR exome AF: 0.000685

Gnomad AMR exome AF: 0.00132

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000814

Gnomad NFE exome AF: 0.00638

Gnomad OTH exome AF: 0.00445

GnomAD4 exome AF: 0.00462 AC: 5043 AN: 1092285 Hom.: 10 Cov.: 28 AF XY: 0.00440 AC XY: 1577 AN XY: 358009

African (AFR) AF: 0.000609 AC: 16 AN: 26289

American (AMR) AF: 0.00137 AC: 48 AN: 35130

Ashkenazi Jewish (ASJ) AF: 0.000103 AC: 2 AN: 19334

East Asian (EAS) AF: 0.00 AC: 0 AN: 30169

South Asian (SAS) AF: 0.000259 AC: 14 AN: 53973

European-Finnish (FIN) AF: 0.00116 AC: 47 AN: 40489

Middle Eastern (MID) AF: 0.000729 AC: 3 AN: 4117

European-Non Finnish (NFE) AF: 0.00564 AC: 4717 AN: 836900

Other (OTH) AF: 0.00427 AC: 196 AN: 45884

GnomAD4 genome AF: 0.00274 AC: 305 AN: 111410 Hom.: 2 Cov.: 22 AF XY: 0.00208 AC XY: 70 AN XY: 33600

African (AFR) AF: 0.000781 AC: 24 AN: 30718

American (AMR) AF: 0.000767 AC: 8 AN: 10424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 2605

European-Finnish (FIN) AF: 0.000167 AC: 1 AN: 5992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00496 AC: 263 AN: 53061

Other (OTH) AF: 0.00199 AC: 3 AN: 1509

Alfa AF: 0.00409 Hom.: 181

Bravo AF: 0.00277

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00312 AC: 9

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00431 AC: 29

ExAC AF: 0.00400 AC: 486

EpiCase AF: 0.00458

EpiControl AF: 0.00547

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Glycogen storage disease IXd (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.0092	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.33
Sift	Benign	0.10	T
Sift4G	Benign	0.11	T
Polyphen		0.034	B
Vest4		0.12
MVP		0.77
MPC		0.38
ClinPred		0.022	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.43
Mutation Taster		=95/5	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: rs139803629; hg19: chrX-71830942; COSMIC: COSV99045068;