15-42329344-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_198141.3(GANC):c.1539T>A(p.Asn513Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GANC NM_198141.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GANC	NM_198141.3	c.1539T>A	p.Asn513Lys	missense_variant	14/24	ENST00000318010.13
GANC	NM_001393928.1	c.1539T>A	p.Asn513Lys	missense_variant	15/25
GANC	NM_001393929.1	c.1539T>A	p.Asn513Lys	missense_variant	15/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GANC	ENST00000318010.13	c.1539T>A	p.Asn513Lys	missense_variant	14/24	1	NM_198141.3	P1
GANC	ENST00000568953.1	n.243T>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251106 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135718

Gnomad AFR exome AF: 0.00

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461672 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727144

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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

Dec 06, 2021

The c.1539T>A (p.N513K) alteration is located in exon 14 (coding exon 14) of the GANC gene. This alteration results from a T to A substitution at nucleotide position 1539, causing the asparagine (N) at amino acid position 513 to be replaced by a lysine (K). 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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.040
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.8	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.91		Loss of catalytic residue at N513 (P = 0.0058);
MVP		0.88
MPC		0.18
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.96
gMVP		0.92

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: rs1208405745; hg19: chr15-42621542;