rs2172397

Variant names:

• chr3-81594016-T-C
• rs2172397
• NM_000158.4:c.1000A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-81594016-T-C
• chr3-81594016-T-A
• chr3-81594016-T-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000158.4(GBE1):​c.1000A>G​(p.Ile334Val) variant causes a missense change. The variant allele was found at a frequency of 0.972 in 1,505,534 control chromosomes in the GnomAD database, including 711,835 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (72929 hom., cov: 31)
  • Exomes 𝑓: 0.97 (638906 hom.)
• Consequence: GBE1 NM_000158.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.82
• Publications: 32 publications found

Genes affected

GBE1 (HGNC:4180): (1,4-alpha-glucan branching enzyme 1) The protein encoded by this gene is a glycogen branching enzyme that catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Branching of the chains is essential to increase the solubility of the glycogen molecule and, consequently, in reducing the osmotic pressure within cells. Highest level of this enzyme are found in liver and muscle. Mutations in this gene are associated with glycogen storage disease IV (also known as Andersen's disease). [provided by RefSeq, Jul 2008]

GBE1 Gene-Disease associations (from GenCC):

• glycogen storage disease due to glycogen branching enzyme deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• adult polyglucosan body disease

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000158.4
• BP4: Computational evidence support a benign effect (MetaRNN=7.2837616E-7).
• BP6: Variant 3-81594016-T-C is Benign according to our data. Variant chr3-81594016-T-C is described in ClinVar as Benign. ClinVar VariationId is 1168034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.988 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000158.4. 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
	GBE1	NM_000158.4	MANE Select	c.1000A>G	p.Ile334Val	missense	Exon 8 of 16	NP_000149.4	Q04446

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBE1	ENST00000429644.7	TSL:1 MANE Select	c.1000A>G	p.Ile334Val	missense	Exon 8 of 16	ENSP00000410833.2	Q04446
	GBE1	ENST00000895874.1		c.1000A>G	p.Ile334Val	missense	Exon 8 of 16	ENSP00000565933.1
	GBE1	ENST00000942742.1		c.994A>G	p.Ile332Val	missense	Exon 8 of 16	ENSP00000612801.1

Frequencies

GnomAD3 genomes AF: 0.979 AC: 148874 AN: 152116 Hom.: 72872 Cov.: 31

Gnomad AFR AF: 0.996

Gnomad AMI AF: 0.996

Gnomad AMR AF: 0.988

Gnomad ASJ AF: 0.986

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.963

Gnomad FIN AF: 0.958

Gnomad MID AF: 0.968

Gnomad NFE AF: 0.969

Gnomad OTH AF: 0.981

GnomAD2 exomes AF: 0.976 AC: 178058 AN: 182518 AF XY: 0.974

Gnomad AFR exome AF: 0.996

Gnomad AMR exome AF: 0.990

Gnomad ASJ exome AF: 0.988

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.959

Gnomad NFE exome AF: 0.969

Gnomad OTH exome AF: 0.978

GnomAD4 exome AF: 0.972 AC: 1314913 AN: 1353300 Hom.: 638906 Cov.: 20 AF XY: 0.971 AC XY: 653309 AN XY: 672632

African (AFR) AF: 0.997 AC: 30979 AN: 31084

American (AMR) AF: 0.990 AC: 37095 AN: 37488

Ashkenazi Jewish (ASJ) AF: 0.985 AC: 24510 AN: 24886

East Asian (EAS) AF: 1.00 AC: 37371 AN: 37374

South Asian (SAS) AF: 0.964 AC: 75296 AN: 78090

European-Finnish (FIN) AF: 0.958 AC: 48660 AN: 50770

Middle Eastern (MID) AF: 0.962 AC: 5405 AN: 5620

European-Non Finnish (NFE) AF: 0.970 AC: 1000433 AN: 1031324

Other (OTH) AF: 0.974 AC: 55164 AN: 56664

GnomAD4 genome AF: 0.979 AC: 148990 AN: 152234 Hom.: 72929 Cov.: 31 AF XY: 0.978 AC XY: 72803 AN XY: 74416

African (AFR) AF: 0.996 AC: 41370 AN: 41554

American (AMR) AF: 0.988 AC: 15090 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.986 AC: 3423 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5169 AN: 5172

South Asian (SAS) AF: 0.962 AC: 4648 AN: 4830

European-Finnish (FIN) AF: 0.958 AC: 10157 AN: 10604

Middle Eastern (MID) AF: 0.966 AC: 284 AN: 294

European-Non Finnish (NFE) AF: 0.969 AC: 65867 AN: 68008

Other (OTH) AF: 0.981 AC: 2074 AN: 2114

Alfa AF: 0.974 Hom.: 145098

Bravo AF: 0.983

TwinsUK AF: 0.972 AC: 3606

ALSPAC AF: 0.972 AC: 3747

ESP6500AA AF: 0.996 AC: 3602

ESP6500EA AF: 0.972 AC: 7924

ExAC AF: 0.969 AC: 112433

Asia WGS AF: 0.984 AC: 3418 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Glycogen storage disease, type IV (3)
-	-	2	Adult polyglucosan body disease (2)
-	-	1	Glycogen storage disease, type IV;C1856301:Glycogen storage disease IV, classic hepatic (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.49
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	7.3e-7	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-3.1	N
PhyloP100		5.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.95	N
REVEL	Benign	0.28
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.062
MPC		0.028
ClinPred		0.012	T
GERP RS		5.7
Varity_R		0.033
gMVP		0.58
Mutation Taster		=98/2	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: rs2172397; hg19: chr3-81643167; COSMIC: COSV107525036;