rs4073918

Variant names:

• chr5-1244310-C-T
• rs4073918
• NM_182632.3:c.1433C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_182632.3(SLC6A18):​c.1433C>T​(p.Pro478Leu) variant causes a missense change. The variant allele was found at a frequency of 0.755 in 1,613,792 control chromosomes in the GnomAD database, including 466,262 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.77 (45815 hom., cov: 31)
  • Exomes 𝑓: 0.75 (420447 hom.)
• Consequence: SLC6A18 NM_182632.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.42

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8419563E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.864 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A18	NM_182632.3	c.1433C>T	p.Pro478Leu	missense_variant	Exon 10 of 12	ENST00000324642.4	NP_872438.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A18	ENST00000324642.4	c.1433C>T	p.Pro478Leu	missense_variant	Exon 10 of 12	1	NM_182632.3	ENSP00000323549.3

Frequencies

GnomAD3 genomes AF: 0.768 AC: 116632 AN: 151910 Hom.: 45771 Cov.: 31

Gnomad AFR AF: 0.871

Gnomad AMI AF: 0.767

Gnomad AMR AF: 0.714

Gnomad ASJ AF: 0.725

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.714

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.771

Gnomad OTH AF: 0.755

GnomAD3 exomes AF: 0.710 AC: 178535 AN: 251440 Hom.: 65737 AF XY: 0.712 AC XY: 96792 AN XY: 135900

Gnomad AFR exome AF: 0.874

Gnomad AMR exome AF: 0.679

Gnomad ASJ exome AF: 0.727

Gnomad EAS exome AF: 0.269

Gnomad SAS exome AF: 0.698

Gnomad FIN exome AF: 0.714

Gnomad NFE exome AF: 0.767

Gnomad OTH exome AF: 0.731

GnomAD4 exome AF: 0.754 AC: 1102313 AN: 1461764 Hom.: 420447 Cov.: 63 AF XY: 0.753 AC XY: 547232 AN XY: 727180

Gnomad4 AFR exome AF: 0.881

Gnomad4 AMR exome AF: 0.687

Gnomad4 ASJ exome AF: 0.726

Gnomad4 EAS exome AF: 0.367

Gnomad4 SAS exome AF: 0.696

Gnomad4 FIN exome AF: 0.719

Gnomad4 NFE exome AF: 0.774

Gnomad4 OTH exome AF: 0.739

GnomAD4 genome AF: 0.768 AC: 116727 AN: 152028 Hom.: 45815 Cov.: 31 AF XY: 0.758 AC XY: 56341 AN XY: 74294

Gnomad4 AFR AF: 0.871

Gnomad4 AMR AF: 0.714

Gnomad4 ASJ AF: 0.725

Gnomad4 EAS AF: 0.278

Gnomad4 SAS AF: 0.688

Gnomad4 FIN AF: 0.714

Gnomad4 NFE AF: 0.771

Gnomad4 OTH AF: 0.748

Alfa AF: 0.759 Hom.: 91311

Bravo AF: 0.772

TwinsUK AF: 0.767 AC: 2843

ALSPAC AF: 0.775 AC: 2987

ESP6500AA AF: 0.863 AC: 3803

ESP6500EA AF: 0.764 AC: 6571

ExAC AF: 0.717 AC: 87057

Asia WGS AF: 0.520 AC: 1813 AN: 3478

EpiCase AF: 0.773

EpiControl AF: 0.765

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Benign	0.79
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0000018	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.5	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	4.9	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.030
MPC		0.16
ClinPred		0.020	T
GERP RS		4.9
Varity_R		0.041
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4073918; hg19: chr5-1244425; COSMIC: COSV57251360;