Genetic Variant SLC16A8:p.Ala500Pro (chr22-38078405-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_013356.3(SLC16A8):c.1498G>C(p.Ala500Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000918 in 1,601,322 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000093 ( 0 hom. )

Consequence

SLC16A8
NM_013356.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.04

Variant links:

Genes affected

SLC16A8 (HGNC:16270): (solute carrier family 16 member 8) SLC16A8 is a member of a family of proton-coupled monocarboxylate transporters that mediate lactate transport across cell membranes (Yoon et al., 1999 [PubMed 10493836]).[supplied by OMIM, Apr 2010]

SLC16A8 links:

LOC105373027 (HGNC:):

LOC105373027 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.017006725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC16A8	NM_013356.3 link	c.1498G>C	p.Ala500Pro	missense_variant	Exon 6 of 6	ENST00000681075.2	NP_037488.2	O95907
SLC16A8	NM_001394131.1 link	c.220G>C	p.Ala74Pro	missense_variant	Exon 2 of 2		NP_001381060.1
SLC16A8	XM_017028685.2 link	c.1498G>C	p.Ala500Pro	missense_variant	Exon 4 of 4		XP_016884174.1	O95907
LOC105373027	XR_938249.3 link	n.-236C>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC16A8	ENST00000681075.2 link	c.1498G>C	p.Ala500Pro	missense_variant	Exon 6 of 6		NM_013356.3	ENSP00000506669.1	O95907
SLC16A8	ENST00000320521.10 link	c.1498G>C	p.Ala500Pro	missense_variant	Exon 5 of 5	1		ENSP00000321735.5	O95907
SLC16A8	ENST00000469516.5 link	n.406G>C		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

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:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000128

AC:

AN:

242708

Hom.:

AF XY:

0.0000908

AC XY:

AN XY:

132106

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000552

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000889

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000932

AC:

135

AN:

1448960

Hom.:

Cov.:

AF XY:

0.0000875

AC XY:

AN XY:

720308

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000695

Gnomad4 ASJ exome

AF:

0.0000768

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000839

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000121

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1498G>C (p.A500P) alteration is located in exon 5 (coding exon 4) of the SLC16A8 gene. This alteration results from a G to C substitution at nucleotide position 1498, causing the alanine (A) at amino acid position 500 to be replaced by a proline (P). 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

0.061

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.63

CADD

Benign

7.0

DANN

Benign

0.85

DEOGEN2

Benign

0.029

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.45

M_CAP

Benign

0.0041

MetaRNN

Benign

0.017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.43

REVEL

Benign

0.024

Sift

Benign

0.27

Sift4G

Benign

0.31

Polyphen

0.10

Vest4

0.13

MutPred

0.11

Gain of relative solvent accessibility (P = 0.09);

MVP

0.16

MPC

0.22

ClinPred

0.021

GERP RS

0.065

Varity_R

0.11

gMVP

0.23

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over