Genetic Variant SLC30A8:p.Val208Leu (chr8-117161787-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_173851.3(SLC30A8):c.622G>C(p.Val208Leu) 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 152,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V208I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

SLC30A8
NM_173851.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.197

Publications

1 publications found

Variant links:

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]

SLC30A8 Gene-Disease associations (from GenCC):

type 2 diabetes mellitus
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

SLC30A8 links:

LOC105375716 (HGNC:):

LOC105375716 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056705087).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173851.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC30A8	NM_173851.3	MANE Select	c.622G>C	p.Val208Leu	missense	Exon 5 of 8	NP_776250.2	Q8IWU4-1
SLC30A8	NM_001172811.2		c.475G>C	p.Val159Leu	missense	Exon 7 of 10	NP_001166282.1	Q8IWU4-2
SLC30A8	NM_001172813.2		c.475G>C	p.Val159Leu	missense	Exon 8 of 11	NP_001166284.1	Q8IWU4-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC30A8	ENST00000456015.7	TSL:1 MANE Select	c.622G>C	p.Val208Leu	missense	Exon 5 of 8	ENSP00000415011.2	Q8IWU4-1
SLC30A8	ENST00000519688.5	TSL:1	c.475G>C	p.Val159Leu	missense	Exon 6 of 9	ENSP00000431069.1	Q8IWU4-2
SLC30A8	ENST00000521243.5	TSL:1	c.475G>C	p.Val159Leu	missense	Exon 7 of 10	ENSP00000428545.1	Q8IWU4-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.55

CADD

Benign

9.5

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.10

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.17

M_CAP

Benign

0.0098

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PhyloP100

0.20

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.60

REVEL

Benign

0.095

Sift

Benign

0.30

Sift4G

Benign

0.36

Polyphen

0.0

Vest4

0.13

MutPred

0.38

Gain of helix (P = 0.132)

MVP

0.56

MPC

0.046

ClinPred

0.024

GERP RS

0.20

Varity_R

0.059

gMVP

0.40

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over