8-117153050-G-C

Variant names:

• chr8-117153050-G-C
• rs779833277
• NM_173851.3:c.378G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_173851.3(SLC30A8):​c.378G>C​(p.Lys126Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,094 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SLC30A8 NM_173851.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.179

Genes affected

SLC30A8 (HGNC:20303): (solute carrier family 30 member 8) The protein encoded by this gene is a zinc efflux transporter involved in the accumulation of zinc in intracellular vesicles. This gene is expressed at a high level only in the pancreas, particularly in islets of Langerhans. The encoded protein colocalizes with insulin in the secretory pathway granules of the insulin-secreting INS-1 cells. Allelic variants of this gene exist that confer susceptibility to diabetes mellitus, noninsulin-dependent (NIDDM). Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]

LOC105375716 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC30A8	NM_173851.3	c.378G>C	p.Lys126Asn	missense_variant	Exon 3 of 8	ENST00000456015.7	NP_776250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC30A8	ENST00000456015.7	c.378G>C	p.Lys126Asn	missense_variant	Exon 3 of 8	1	NM_173851.3	ENSP00000415011.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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 Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74282

Gnomad4 AFR AF: 0.0000242

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

Submissions by phenotype

not specified Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.378G>C (p.K126N) alteration is located in exon 3 (coding exon 3) of the SLC30A8 gene. This alteration results from a G to C substitution at nucleotide position 378, causing the lysine (K) at amino acid position 126 to be replaced by an asparagine (N). 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	0.61
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T;.;.;D
Eigen	Benign	0.048
Eigen_PC	Benign	-0.057
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	.;D;T;.;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.46	T;T;T;T;T
MetaSVM	Uncertain	-0.050	T
MutationAssessor	Uncertain	2.7	.;.;.;.;M
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	N;D;N;N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.034	D;T;D;D;D
Polyphen		0.59	.;.;.;.;P
Vest4		0.46
MutPred		0.61		.;.;.;.;Loss of ubiquitination at K126 (P = 0.0362);
MVP		0.63
MPC		0.28
ClinPred		0.98	D
GERP RS		1.1
Varity_R		0.46
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs779833277; hg19: chr8-118165289;