rs187710792

Variant names:

• chr16-30756210-G-A
• rs187710792
• NM_000294.3:c.585G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The ENST00000563588.6(PHKG2):​c.585G>A​(p.Ala195Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000242 in 1,614,070 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (7 hom.)
• Consequence: PHKG2 ENST00000563588.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.0980
• Publications: 2 publications found

Genes affected

PHKG2 (HGNC:8931): (phosphorylase kinase catalytic subunit gamma 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, encoded by two different genes. 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, and the hepatic isoform is encoded by this gene. 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 9C, also known as autosomal liver glycogenosis. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene.[provided by RefSeq, Feb 2010]

PHKG2 Gene-Disease associations (from GenCC):

• glycogen storage disease IXc

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• glycogen storage disease due to liver phosphorylase kinase deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 16-30756210-G-A is Benign according to our data. Variant chr16-30756210-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255785.
• BP7: Synonymous conserved (PhyloP=-0.098 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000361 (55/152222) while in subpopulation EAS AF = 0.0027 (14/5190). AF 95% confidence interval is 0.00163. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000563588.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKG2	NM_000294.3	MANE Select	c.585G>A	p.Ala195Ala	synonymous	Exon 7 of 10	NP_000285.1
	PHKG2	NM_001172432.2		c.585G>A	p.Ala195Ala	synonymous	Exon 7 of 11	NP_001165903.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKG2	ENST00000563588.6	TSL:1 MANE Select	c.585G>A	p.Ala195Ala	synonymous	Exon 7 of 10	ENSP00000455607.1
	PHKG2	ENST00000328273.11	TSL:5	c.585G>A	p.Ala195Ala	synonymous	Exon 7 of 10	ENSP00000329968.7
	PHKG2	ENST00000424889.7	TSL:2	c.585G>A	p.Ala195Ala	synonymous	Exon 7 of 11	ENSP00000388571.3

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000406 AC: 102 AN: 251496 AF XY: 0.000449

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00256

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000230 AC: 336 AN: 1461848 Hom.: 7 Cov.: 33 AF XY: 0.000223 AC XY: 162 AN XY: 727226

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00329 AC: 86 AN: 26136

East Asian (EAS) AF: 0.00141 AC: 56 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111978

Other (OTH) AF: 0.00245 AC: 148 AN: 60394

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74430

African (AFR) AF: 0.000530 AC: 22 AN: 41524

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67988

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000486 Hom.: 0

Bravo AF: 0.000487

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		-0.098
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=91/9	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: rs187710792; hg19: chr16-30767531;