NM_002637.4:c.3072+2150T>C

Variant names:

• chrX-72599841-A-G
• rs7054230
• NM_002637.4:c.3072+2150T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002637.4(PHKA1):​c.3072+2150T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 549,092 control chromosomes in the GnomAD database, including 8,874 homozygotes. There are 21,183 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1674 hom., 4368 hem., cov: 22)
  • Exomes 𝑓: 0.11 (7200 hom. 16815 hem.)
• Consequence: PHKA1 NM_002637.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0210
• Publications: 6 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: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.3429835E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA1	NM_002637.4	c.3072+2150T>C		intron_variant	Intron 28 of 31	ENST00000373542.9	NP_002628.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKA1	ENST00000373542.9	c.3072+2150T>C		intron_variant	Intron 28 of 31	1	NM_002637.4	ENSP00000362643.4

Frequencies

GnomAD3 genomes AF: 0.133 AC: 14689 AN: 110438 Hom.: 1675 Cov.: 22

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.0327

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00921

Gnomad OTH AF: 0.132

GnomAD2 exomes AF: 0.165 AC: 24100 AN: 145859 AF XY: 0.133

Gnomad AFR exome AF: 0.287

Gnomad AMR exome AF: 0.395

Gnomad ASJ exome AF: 0.0245

Gnomad EAS exome AF: 0.679

Gnomad FIN exome AF: 0.0261

Gnomad NFE exome AF: 0.00939

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.110 AC: 48276 AN: 438600 Hom.: 7200 Cov.: 0 AF XY: 0.106 AC XY: 16815 AN XY: 158758

African (AFR) AF: 0.280 AC: 3771 AN: 13461

American (AMR) AF: 0.383 AC: 12274 AN: 32047

Ashkenazi Jewish (ASJ) AF: 0.0283 AC: 426 AN: 15031

East Asian (EAS) AF: 0.688 AC: 18215 AN: 26488

South Asian (SAS) AF: 0.196 AC: 7581 AN: 38664

European-Finnish (FIN) AF: 0.0269 AC: 1035 AN: 38476

Middle Eastern (MID) AF: 0.0526 AC: 158 AN: 3001

European-Non Finnish (NFE) AF: 0.00984 AC: 2432 AN: 247207

Other (OTH) AF: 0.0984 AC: 2384 AN: 24225

GnomAD4 genome AF: 0.133 AC: 14696 AN: 110492 Hom.: 1674 Cov.: 22 AF XY: 0.133 AC XY: 4368 AN XY: 32800

African (AFR) AF: 0.276 AC: 8348 AN: 30268

American (AMR) AF: 0.249 AC: 2564 AN: 10310

Ashkenazi Jewish (ASJ) AF: 0.0327 AC: 86 AN: 2631

East Asian (EAS) AF: 0.672 AC: 2315 AN: 3445

South Asian (SAS) AF: 0.213 AC: 553 AN: 2595

European-Finnish (FIN) AF: 0.0221 AC: 132 AN: 5975

Middle Eastern (MID) AF: 0.0556 AC: 12 AN: 216

European-Non Finnish (NFE) AF: 0.00921 AC: 487 AN: 52876

Other (OTH) AF: 0.134 AC: 199 AN: 1490

Alfa AF: 0.0682 Hom.: 980

Bravo AF: 0.169

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00935 AC: 27

ESP6500AA AF: 0.287 AC: 407

ESP6500EA AF: 0.00967 AC: 30

ExAC AF: 0.146 AC: 16573

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.8
DANN	Benign	0.24
DEOGEN2	Benign	0.0058	T;T
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.52	T;T
MetaRNN	Benign	0.0000093	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.021
PROVEAN	Benign	0.010	N;N
REVEL	Benign	0.073
Sift	Benign	0.57	T;T
Sift4G	Benign	0.63	T;T
Vest4		0.098
ClinPred		0.0057	T
GERP RS		1.3
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs7054230; hg19: chrX-71819691;