15-42292816-C-A

Position:

chr15-42292816-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_198141.3(GANC):c.411C>A(p.Asn137Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,990 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GANC
NM_198141.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.114

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.16004503).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GANC	NM_198141.3 linkuse as main transcript	c.411C>A	p.Asn137Lys	missense_variant	5/24	ENST00000318010.13	NP_937784.2
GANC	NM_001393928.1 linkuse as main transcript	c.411C>A	p.Asn137Lys	missense_variant	6/25		NP_001380857.1
GANC	NM_001393929.1 linkuse as main transcript	c.411C>A	p.Asn137Lys	missense_variant	6/25		NP_001380858.1
GANC	NM_001301409.2 linkuse as main transcript	c.411C>A	p.Asn137Lys	missense_variant	6/12		NP_001288338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
GANC	ENST00000318010.13 linkuse as main transcript	c.411C>A	p.Asn137Lys	missense_variant	5/24	1	NM_198141.3	ENSP00000326227	P1
GANC	ENST00000566442.5 linkuse as main transcript	c.411C>A	p.Asn137Lys	missense_variant	6/12	2		ENSP00000454747
GANC	ENST00000562859.5 linkuse as main transcript	c.411C>A	p.Asn137Lys	missense_variant	6/6	5		ENSP00000454449
GANC	ENST00000567421.1 linkuse as main transcript	n.384C>A		non_coding_transcript_exon_variant	4/12	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2021

The c.411C>A (p.N137K) alteration is located in exon 5 (coding exon 5) of the GANC gene. This alteration results from a C to A substitution at nucleotide position 411, causing the asparagine (N) at amino acid position 137 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

Benign

0.097

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

5.2

DANN

Benign

0.46

DEOGEN2

Benign

0.078

T;.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.68

T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.94

.;.;L

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.22

T;T;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.27, 0.27

MutPred

0.46

Gain of ubiquitination at N137 (P = 0.0192);Gain of ubiquitination at N137 (P = 0.0192);Gain of ubiquitination at N137 (P = 0.0192);

MVP

0.55

MPC

0.022

ClinPred

0.077

GERP RS

1.2

Varity_R

0.024

gMVP

0.42

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over