15-42308288-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198141.3(GANC):c.692A>G(p.His231Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000756 in 1,609,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (0 hom.)
• Consequence: GANC NM_198141.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.59

Genes affected

GANC (HGNC:4139): (glucosidase alpha, neutral C) Glycosyl hydrolase enzymes hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. This gene encodes a member of glycosyl hydrolases family 31. This enzyme hydrolyses terminal, non-reducing 1,4-linked alpha-D-glucose residues and releases alpha-D-glucose. This is a key enzyme in glycogen metabolism and its gene localizes to a chromosomal region (15q15) that is associated with susceptibility to diabetes. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19018453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GANC	NM_198141.3	c.692A>G	p.His231Arg	missense_variant	8/24	ENST00000318010.13
GANC	NM_001393928.1	c.692A>G	p.His231Arg	missense_variant	9/25
GANC	NM_001393929.1	c.692A>G	p.His231Arg	missense_variant	9/25
GANC	NM_001301409.2	c.692A>G	p.His231Arg	missense_variant	9/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GANC	ENST00000318010.13	c.692A>G	p.His231Arg	missense_variant	8/24	1	NM_198141.3	P1
GANC	ENST00000566442.5	c.692A>G	p.His231Arg	missense_variant	9/12	2
GANC	ENST00000567421.1	n.665A>G		non_coding_transcript_exon_variant	7/12	5

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000359 AC: 90 AN: 251038 Hom.: 0 AF XY: 0.000420 AC XY: 57 AN XY: 135662

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.000617

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000789 AC: 1150 AN: 1457014 Hom.: 0 Cov.: 29 AF XY: 0.000760 AC XY: 551 AN XY: 724718

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000582

Gnomad4 NFE exome AF: 0.000937

Gnomad4 OTH exome AF: 0.00125

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74374

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000808

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000645 Hom.: 0

Bravo AF: 0.000461

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000255 AC: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

The c.692A>G (p.H231R) alteration is located in exon 8 (coding exon 8) of the GANC gene. This alteration results from a A to G substitution at nucleotide position 692, causing the histidine (H) at amino acid position 231 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	23
Dann	Uncertain	0.99
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Uncertain	0.066	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.7	D;D
Sift	Uncertain	0.028	D;D
Sift4G	Benign	0.34	T;T
Polyphen		0.23	.;B
Vest4		0.50
MVP		0.69
MPC		0.040
ClinPred		0.18	T
GERP RS		4.5
Varity_R		0.71
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs145199858; hg19: chr15-42600486;