rs16889462

chr8-117172545-G-Achr8-117172545-G-Cchr8-117172545-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_173851.3(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 (★). 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 NM_173851.3 missense
• Clinical Significance: Benign criteria provided, single submitter 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 -14 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 criteria_provided_single_submitter, 1 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	UniProt
SLC30A8	NM_173851.3	c.974G>A	p.Arg325Gln	missense_variant	8/8	ENST00000456015.7
LOC105375716	XR_007061067.1	n.819+70C>T		intron_variant, non_coding_transcript_variant

Ensembl

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

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: criteria provided, single submitter

Submissions by phenotype

SLC30A8-related disorder Benign:1

Benign, criteria provided, single submitter

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
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.091	N
MetaRNN	Benign	0.0015	T;T;T;T
MetaSVM	Benign	-1.1	T
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;