5-1235629-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_182632.3(SLC6A18):c.588G>A(p.Met196Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00717 in 1,613,974 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0051 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0074 (35 hom.)
• Consequence: SLC6A18 NM_182632.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.872

Genes affected

SLC6A18 (HGNC:26441): (solute carrier family 6 member 18) The SLC6 family of proteins, which includes SLC6A18, act as specific transporters for neurotransmitters, amino acids, and osmolytes like betaine, taurine, and creatine. SLC6 proteins are sodium cotransporters that derive the energy for solute transport from the electrochemical gradient for sodium ions (Hoglund et al., 2005 [PubMed 16125675]).[supplied by OMIM, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0099232495).
• BP6: Variant 5-1235629-G-A is Benign according to our data. Variant chr5-1235629-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2655271.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A18	NM_182632.3	c.588G>A	p.Met196Ile	missense_variant	4/12	ENST00000324642.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A18	ENST00000324642.4	c.588G>A	p.Met196Ile	missense_variant	4/12	1	NM_182632.3	P1

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 783 AN: 152190 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00819

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00794

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00506 AC: 1271 AN: 251320 Hom.: 4 AF XY: 0.00511 AC XY: 694 AN XY: 135836

Gnomad AFR exome AF: 0.00222

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00212

Gnomad FIN exome AF: 0.00744

Gnomad NFE exome AF: 0.00809

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00738 AC: 10785 AN: 1461666 Hom.: 35 Cov.: 31 AF XY: 0.00714 AC XY: 5193 AN XY: 727126

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00192

Gnomad4 FIN exome AF: 0.00836

Gnomad4 NFE exome AF: 0.00867

Gnomad4 OTH exome AF: 0.00671

GnomAD4 genome AF: 0.00514 AC: 783 AN: 152308 Hom.: 3 Cov.: 33 AF XY: 0.00534 AC XY: 398 AN XY: 74476

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00819

Gnomad4 NFE AF: 0.00794

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00643 Hom.: 9

Bravo AF: 0.00461

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.00501 AC: 608

EpiCase AF: 0.00780

EpiControl AF: 0.00699

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

SLC6A18: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	12
Dann	Benign	0.80
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.68	N
MutationTaster	Benign	0.62	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.77	N
REVEL	Benign	0.19
Sift	Benign	0.28	T
Sift4G	Benign	0.39	T
Polyphen		0.0030	B
Vest4		0.12
MutPred		0.64		Loss of methylation at R200 (P = 0.18);
MVP		0.64
MPC		0.18
ClinPred		0.012	T
GERP RS		4.5
Varity_R		0.15
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76827400; hg19: chr5-1235744; COSMIC: COSV57250356; COSMIC: COSV57250356;