15-42292803-A-G

Position:

• chr15-42292803-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198141.3(GANC):​c.398A>G​(p.His133Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: GANC NM_198141.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.735

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]

GANC (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.064747065).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GANC	NM_198141.3	c.398A>G	p.His133Arg	missense_variant	5/24	ENST00000318010.13	NP_937784.2
GANC	NM_001393928.1	c.398A>G	p.His133Arg	missense_variant	6/25		NP_001380857.1
GANC	NM_001393929.1	c.398A>G	p.His133Arg	missense_variant	6/25		NP_001380858.1
GANC	NM_001301409.2	c.398A>G	p.His133Arg	missense_variant	6/12		NP_001288338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GANC	ENST00000318010.13	c.398A>G	p.His133Arg	missense_variant	5/24	1	NM_198141.3	ENSP00000326227.8
GANC	ENST00000566442.5	c.398A>G	p.His133Arg	missense_variant	6/12	2		ENSP00000454747.1
GANC	ENST00000562859.5	c.398A>G	p.His133Arg	missense_variant	6/6	5		ENSP00000454449.1
GANC	ENST00000567421.1	n.371A>G		non_coding_transcript_exon_variant	4/12	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461832 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

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

Sep 11, 2024

The c.398A>G (p.H133R) alteration is located in exon 5 (coding exon 5) of the GANC gene. This alteration results from a A to G substitution at nucleotide position 398, causing the histidine (H) at amino acid position 133 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	0.062
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.0
DANN	Benign	0.83
DEOGEN2	Benign	0.079	T;.;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.60	T;T;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.065	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;.;L
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.022
Sift	Benign	0.054	T;T;T
Sift4G	Benign	0.74	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.091, 0.10
MVP		0.16
MPC		0.022
ClinPred		0.056	T
GERP RS		2.8
Varity_R		0.020
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-42585001;