5-1232330-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_182632.3(SLC6A18):c.272C>T(p.Thr91Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,611,678 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T91S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (36 hom., cov: 34)
  • Exomes 𝑓: 0.0012 (36 hom.)
• Consequence: SLC6A18 NM_182632.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.99

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00369367).
• BP6: Variant 5-1232330-C-T is Benign according to our data. Variant chr5-1232330-C-T is described in ClinVar as [Benign]. Clinvar id is 791254.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.012 (1832/152346) while in subpopulation AFR AF= 0.0421 (1750/41562). AF 95% confidence interval is 0.0405. There are 36 homozygotes in gnomad4. There are 867 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A18	NM_182632.3	c.272C>T	p.Thr91Met	missense_variant	2/12	ENST00000324642.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A18	ENST00000324642.4	c.272C>T	p.Thr91Met	missense_variant	2/12	1	NM_182632.3	P1
SLC6A18	ENST00000513607.2	n.341C>T		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1829 AN: 152228 Hom.: 36 Cov.: 34

Gnomad AFR AF: 0.0421

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00300 AC: 734 AN: 244518 Hom.: 9 AF XY: 0.00236 AC XY: 313 AN XY: 132858

Gnomad AFR exome AF: 0.0408

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000200

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000909

Gnomad OTH exome AF: 0.00235

GnomAD4 exome AF: 0.00119 AC: 1743 AN: 1459332 Hom.: 36 Cov.: 39 AF XY: 0.00109 AC XY: 794 AN XY: 725856

Gnomad4 AFR exome AF: 0.0408

Gnomad4 AMR exome AF: 0.00262

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000222

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.00279

GnomAD4 genome AF: 0.0120 AC: 1832 AN: 152346 Hom.: 36 Cov.: 34 AF XY: 0.0116 AC XY: 867 AN XY: 74492

Gnomad4 AFR AF: 0.0421

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00394 Hom.: 12

Bravo AF: 0.0134

ESP6500AA AF: 0.0368 AC: 162

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00384 AC: 465

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	1.7
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.022	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0037	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.057	T
Polyphen		1.0	D
Vest4		0.31
MVP		0.46
MPC		0.22
ClinPred		0.050	T
GERP RS		-9.3
Varity_R		0.12
gMVP		0.27

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

Other links and lift over

dbSNP: rs10055742; hg19: chr5-1232445; COSMIC: COSV57254952;