15-42292805-A-C

Variant summary

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

The NM_198141.3(GANC):c.400A>C(p.Ile134Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: GANC NM_198141.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0470

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047542453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GANC	NM_198141.3	c.400A>C	p.Ile134Leu	missense_variant	5/24	ENST00000318010.13
GANC	NM_001393928.1	c.400A>C	p.Ile134Leu	missense_variant	6/25
GANC	NM_001393929.1	c.400A>C	p.Ile134Leu	missense_variant	6/25
GANC	NM_001301409.2	c.400A>C	p.Ile134Leu	missense_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GANC	ENST00000318010.13	c.400A>C	p.Ile134Leu	missense_variant	5/24	1	NM_198141.3	P1
GANC	ENST00000566442.5	c.400A>C	p.Ile134Leu	missense_variant	6/12	2
GANC	ENST00000562859.5	c.400A>C	p.Ile134Leu	missense_variant	6/6	5
GANC	ENST00000567421.1	n.373A>C		non_coding_transcript_exon_variant	4/12	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

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

Aug 15, 2023

The c.400A>C (p.I134L) alteration is located in exon 5 (coding exon 5) of the GANC gene. This alteration results from a A to C substitution at nucleotide position 400, causing the isoleucine (I) at amino acid position 134 to be replaced by a leucine (L). 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	0.12
BayesDel_addAF	Benign	-0.0076	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	1.8
Dann	Benign	0.50
DEOGEN2	Benign	0.078	T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.058	N
LIST_S2	Uncertain	0.86	D;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.048	T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.61	N;N;N
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.34, 0.35
MutPred		0.51		Gain of ubiquitination at K131 (P = 0.0737);Gain of ubiquitination at K131 (P = 0.0737);Gain of ubiquitination at K131 (P = 0.0737);
MVP		0.24
MPC		0.022
ClinPred		0.040	T
GERP RS		-1.4
Varity_R		0.030
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr15-42585003; COSMIC: COSV58807704;