Genetic Variant SLC6A16:p.Gly519Ser (chr19-49293890-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014037.3(SLC6A16):c.1555G>A(p.Gly519Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G519V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

SLC6A16
NM_014037.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.79

Variant links:

Genes affected

SLC6A16 (HGNC:13622): (solute carrier family 6 member 16) SLC6A16 shows structural characteristics of an Na(+)- and Cl(-)-dependent neurotransmitter transporter, including 12 transmembrane (TM) domains, intracellular N and C termini, and large extracellular loops containing multiple N-glycosylation sites.[supplied by OMIM, Mar 2008]

SLC6A16 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A16	NM_014037.3 link	c.1555G>A	p.Gly519Ser	missense_variant	Exon 9 of 12	ENST00000335875.9	NP_054756.2	Q9GZN6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC6A16	ENST00000335875.9 link	c.1555G>A	p.Gly519Ser	missense_variant	Exon 9 of 12	5	NM_014037.3	ENSP00000338627.3	Q9GZN6-1
SLC6A16	ENST00000454748.7 link	c.1555G>A	p.Gly519Ser	missense_variant	Exon 9 of 11	1		ENSP00000404022.2	Q9GZN6-2
SLC6A16	ENST00000598828.1 link	c.190G>A	p.Gly64Ser	missense_variant	Exon 3 of 5	2		ENSP00000469885.1	M0QYK3
SLC6A16	ENST00000598221.1 link	n.411G>A		non_coding_transcript_exon_variant	Exon 3 of 4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249542

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135388

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1555G>A (p.G519S) alteration is located in exon 9 (coding exon 8) of the SLC6A16 gene. This alteration results from a G to A substitution at nucleotide position 1555, causing the glycine (G) at amino acid position 519 to be replaced by a serine (S). 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

0.17

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.24

T;.;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.57

T;T;T

M_CAP

Benign

0.022

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.7

L;L;.

PrimateAI

Benign

0.27

PROVEAN

Pathogenic

-5.4

D;D;.

REVEL

Benign

0.25

Sift

Benign

0.057

T;T;.

Sift4G

Benign

0.11

T;T;.

Polyphen

1.0

D;.;.

Vest4

0.26

MutPred

0.89

Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;

MVP

0.83

MPC

0.69

ClinPred

0.76

GERP RS

0.033

Varity_R

0.26

gMVP

0.33

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