rs34667348

Variant names:

• chr16-47650919-C-A
• rs34667348
• NM_000293.3:c.1969C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-47650919-C-A
• chr16-47650919-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000293.3(PHKB):​c.1969C>A​(p.Gln657Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0038 in 1,604,956 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q657H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (15 hom.)
• Consequence: PHKB NM_000293.3 missense, splice_region
• Scores: Splicing: ADA: 0.05761
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5 O:1
• Conservation: PhyloP100: 7.26
• Publications: 20 publications found

Genes affected

PHKB (HGNC:8927): (phosphorylase kinase regulatory subunit beta) 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, encoded by this gene, which is a member of the phosphorylase b kinase regulatory subunit family. The gamma subunit also includes the skeletal muscle and hepatic isoforms, 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 9B, also known as phosphorylase kinase deficiency of liver and muscle. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene. Two pseudogenes have been found on chromosomes 14 and 20, respectively.[provided by RefSeq, Feb 2010]

PHKB Gene-Disease associations (from GenCC):

• glycogen storage disease IXb

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026981533).
• BP6: Variant 16-47650919-C-A is Benign according to our data. Variant chr16-47650919-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 281127.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00282 (429/152312) while in subpopulation NFE AF = 0.00525 (357/68020). AF 95% confidence interval is 0.0048. There are 2 homozygotes in GnomAd4. There are 185 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000293.3. 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
	PHKB	NM_000293.3	MANE Select	c.1969C>A	p.Gln657Lys	missense splice_region	Exon 20 of 31	NP_000284.1	Q93100-1
	PHKB	NM_001363837.1		c.1969C>A	p.Gln657Lys	missense splice_region	Exon 20 of 31	NP_001350766.1	Q93100-3
	PHKB	NM_001031835.3		c.1948C>A	p.Gln650Lys	missense splice_region	Exon 21 of 32	NP_001027005.1	Q93100-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKB	ENST00000323584.10	TSL:1 MANE Select	c.1969C>A	p.Gln657Lys	missense splice_region	Exon 20 of 31	ENSP00000313504.5	Q93100-1
	PHKB	ENST00000566044.5	TSL:1	c.1948C>A	p.Gln650Lys	missense splice_region	Exon 21 of 32	ENSP00000456729.1	Q93100-4
	PHKB	ENST00000940565.1		c.2047C>A	p.Gln683Lys	missense splice_region	Exon 20 of 31	ENSP00000610624.1

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 429 AN: 152194 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00525

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00276 AC: 694 AN: 251224 AF XY: 0.00291

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00525

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00390 AC: 5669 AN: 1452644 Hom.: 15 Cov.: 29 AF XY: 0.00379 AC XY: 2740 AN XY: 723288

African (AFR) AF: 0.000721 AC: 24 AN: 33292

American (AMR) AF: 0.00121 AC: 54 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86080

European-Finnish (FIN) AF: 0.00155 AC: 83 AN: 53402

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5750

European-Non Finnish (NFE) AF: 0.00485 AC: 5352 AN: 1103604

Other (OTH) AF: 0.00218 AC: 131 AN: 60096

GnomAD4 genome AF: 0.00282 AC: 429 AN: 152312 Hom.: 2 Cov.: 32 AF XY: 0.00248 AC XY: 185 AN XY: 74486

African (AFR) AF: 0.000794 AC: 33 AN: 41574

American (AMR) AF: 0.00157 AC: 24 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00525 AC: 357 AN: 68020

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00398 Hom.: 4

Bravo AF: 0.00283

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00290 AC: 352

EpiCase AF: 0.00387

EpiControl AF: 0.00362

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	Glycogen storage disease IXb (5)
-	3	1	not provided (4)
-	-	1	not specified (1)
-	-	1	PHKB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.027	T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	1.7	L
PhyloP100		7.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.76
MVP		0.91
MPC		0.63
ClinPred		0.017	T
GERP RS		4.8
Varity_R		0.61
gMVP		0.83
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.058
dbscSNV1_RF	Benign	0.36
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: rs34667348; hg19: chr16-47684830;