15-42292901-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_198141.3(GANC):c.496A>G(p.Ile166Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00486 in 1,613,948 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0081 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (68 hom.)
• Consequence: GANC NM_198141.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.222

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022723973).
• BP6: Variant 15-42292901-A-G is Benign according to our data. Variant chr15-42292901-A-G is described in ClinVar as [Benign]. Clinvar id is 769877.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00808 (1231/152352) while in subpopulation SAS AF= 0.0226 (109/4832). AF 95% confidence interval is 0.0191. There are 9 homozygotes in gnomad4. There are 629 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GANC	NM_198141.3	c.496A>G	p.Ile166Val	missense_variant	5/24	ENST00000318010.13
GANC	NM_001393928.1	c.496A>G	p.Ile166Val	missense_variant	6/25
GANC	NM_001393929.1	c.496A>G	p.Ile166Val	missense_variant	6/25
GANC	NM_001301409.2	c.496A>G	p.Ile166Val	missense_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GANC	ENST00000318010.13	c.496A>G	p.Ile166Val	missense_variant	5/24	1	NM_198141.3	P1
GANC	ENST00000566442.5	c.496A>G	p.Ile166Val	missense_variant	6/12	2
GANC	ENST00000567421.1	n.469A>G		non_coding_transcript_exon_variant	4/12	5

Frequencies

GnomAD3 genomes AF: 0.00806 AC: 1227 AN: 152234 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.0283

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0225

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00282

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00742 AC: 1863 AN: 251120 Hom.: 20 AF XY: 0.00833 AC XY: 1131 AN XY: 135718

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.00605

Gnomad ASJ exome AF: 0.0289

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0218

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00346

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00453 AC: 6617 AN: 1461596 Hom.: 68 Cov.: 33 AF XY: 0.00522 AC XY: 3793 AN XY: 727080

Gnomad4 AFR exome AF: 0.0164

Gnomad4 AMR exome AF: 0.00626

Gnomad4 ASJ exome AF: 0.0275

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0222

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00221

Gnomad4 OTH exome AF: 0.00866

GnomAD4 genome AF: 0.00808 AC: 1231 AN: 152352 Hom.: 9 Cov.: 33 AF XY: 0.00844 AC XY: 629 AN XY: 74502

Gnomad4 AFR AF: 0.0151

Gnomad4 AMR AF: 0.0110

Gnomad4 ASJ AF: 0.0283

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0226

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00282

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.00551 Hom.: 23

Bravo AF: 0.00904

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.0143 AC: 63

ESP6500EA AF: 0.00454 AC: 39

ExAC AF: 0.00753 AC: 914

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.00453

EpiControl AF: 0.00486

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.75
Dann	Benign	0.54
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.63	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.47	N;N
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.051
MVP		0.21
MPC		0.020
ClinPred		0.0015	T
GERP RS		0.39
Varity_R		0.016
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs16973015; hg19: chr15-42585099;