15-42287751-G-A

Position:

• chr15-42287751-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198141.3(GANC):​c.262G>A​(p.Glu88Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00991 in 1,613,020 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (8 hom., cov: 32)
  • Exomes 𝑓: 0.010 (106 hom.)
• Consequence: GANC NM_198141.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.67

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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: BayesDel_noAF, Cadd, Dann, Eigen, FATHMM_MKL, REVEL [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.007130444).
• BP6: Variant 15-42287751-G-A is Benign according to our data. Variant chr15-42287751-G-A is described in ClinVar as [Benign]. Clinvar id is 775354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0102 (14863/1460886) while in subpopulation MID AF= 0.0189 (109/5762). AF 95% confidence interval is 0.016. There are 106 homozygotes in gnomad4_exome. There are 7523 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GANC	NM_198141.3	c.262G>A	p.Glu88Lys	missense_variant	4/24	ENST00000318010.13	NP_937784.2
GANC	NM_001393928.1	c.262G>A	p.Glu88Lys	missense_variant	5/25		NP_001380857.1
GANC	NM_001393929.1	c.262G>A	p.Glu88Lys	missense_variant	5/25		NP_001380858.1
GANC	NM_001301409.2	c.262G>A	p.Glu88Lys	missense_variant	5/12		NP_001288338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GANC	ENST00000318010.13	c.262G>A	p.Glu88Lys	missense_variant	4/24	1	NM_198141.3	ENSP00000326227	P1

Frequencies

GnomAD3 genomes AF: 0.00743 AC: 1129 AN: 152016 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00662

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00812 AC: 2037 AN: 250902 Hom.: 25 AF XY: 0.00859 AC XY: 1165 AN XY: 135620

Gnomad AFR exome AF: 0.00247

Gnomad AMR exome AF: 0.00366

Gnomad ASJ exome AF: 0.00746

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00906

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0102 AC: 14863 AN: 1460886 Hom.: 106 Cov.: 33 AF XY: 0.0104 AC XY: 7523 AN XY: 726768

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.00388

Gnomad4 ASJ exome AF: 0.00670

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0106

Gnomad4 FIN exome AF: 0.00283

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.00852

GnomAD4 genome AF: 0.00740 AC: 1126 AN: 152134 Hom.: 8 Cov.: 32 AF XY: 0.00677 AC XY: 504 AN XY: 74402

Gnomad4 AFR AF: 0.00207

Gnomad4 AMR AF: 0.00661

Gnomad4 ASJ AF: 0.00577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00829

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.0109 Hom.: 20

Bravo AF: 0.00734

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00896 AC: 77

ExAC AF: 0.00867 AC: 1053

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0142

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 20, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D;.;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D
MetaRNN	Benign	0.0071	T;T;T
MetaSVM	Uncertain	-0.028	T
MutationAssessor	Uncertain	2.3	.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.76, 0.72
MVP		0.86
MPC		0.18
ClinPred		0.021	T
GERP RS		5.4
Varity_R		0.45
gMVP		0.83

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: rs145853612; hg19: chr15-42579949; COSMIC: COSV58807263; COSMIC: COSV58807263;