rs16889462

Positions:

• chr8-117172545-G-A
• chr8-117172545-G-C
• chr8-117172545-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000456015.7(SLC30A8):​c.974G>A​(p.Arg325Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00792 in 1,613,552 control chromosomes in the GnomAD database, including 567 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 (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R325W) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.033 (248 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (319 hom.)
• Consequence: SLC30A8 ENST00000456015.7 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0580

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014527738).
• BP6: Variant 8-117172545-G-A is Benign according to our data. Variant chr8-117172545-G-A is described in ClinVar as [Benign]. Clinvar id is 3038448.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC30A8	NM_173851.3	c.974G>A	p.Arg325Gln	missense_variant	8/8	ENST00000456015.7	NP_776250.2
LOC105375716	XR_007061067.1	n.819+70C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC30A8	ENST00000456015.7	c.974G>A	p.Arg325Gln	missense_variant	8/8	1	NM_173851.3	ENSP00000415011	P1
SLC30A8	ENST00000519688.5	c.827G>A	p.Arg276Gln	missense_variant	9/9	1		ENSP00000431069
SLC30A8	ENST00000521243.5	c.827G>A	p.Arg276Gln	missense_variant	10/10	1		ENSP00000428545
SLC30A8	ENST00000427715.2	c.827G>A	p.Arg276Gln	missense_variant	11/11	2		ENSP00000407505

Frequencies

GnomAD3 genomes AF: 0.0330 AC: 5017 AN: 152116 Hom.: 242 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0722

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0248

GnomAD3 exomes AF: 0.0145 AC: 3620 AN: 249532 Hom.: 163 AF XY: 0.0122 AC XY: 1653 AN XY: 134998

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.00576

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0798

Gnomad SAS exome AF: 0.00294

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000679

Gnomad OTH exome AF: 0.00605

GnomAD4 exome AF: 0.00530 AC: 7743 AN: 1461318 Hom.: 319 Cov.: 34 AF XY: 0.00491 AC XY: 3568 AN XY: 726974

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.00667

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.0604

Gnomad4 SAS exome AF: 0.00306

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.000368

Gnomad4 OTH exome AF: 0.0119

GnomAD4 genome AF: 0.0331 AC: 5041 AN: 152234 Hom.: 248 Cov.: 33 AF XY: 0.0327 AC XY: 2431 AN XY: 74440

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.0124

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.0721

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.00525 Hom.: 56

Bravo AF: 0.0372

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.102 AC: 449

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.0163 AC: 1975

Asia WGS AF: 0.0430 AC: 150 AN: 3476

EpiCase AF: 0.000655

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

SLC30A8-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Benign	0.096	.;.;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.16	.;T;.;T
MetaRNN	Benign	0.0015	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.070	.;.;.;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-0.12	N;N;N;N
REVEL	Benign	0.030
Sift	Benign	0.099	T;T;T;T
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.0040	.;.;.;B
Vest4		0.035
MPC		0.051
ClinPred		0.0057	T
GERP RS		-2.3
Varity_R		0.068
gMVP		0.28

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: rs16889462; hg19: chr8-118184784; COSMIC: COSV69973661;