rs6352

Positions:

chr17-30203175-T-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBS1BS2_Supporting

The NM_001045.6(SLC6A4):c.1815A>C(p.Lys605Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,612,818 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 12 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 81 hom. )

Consequence

SLC6A4
NM_001045.6 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.852

Variant links:

Genes affected

SLC6A4 (HGNC:11050): (solute carrier family 6 member 4) This gene encodes an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. The encoded protein terminates the action of serotonin and recycles it in a sodium-dependent manner. This protein is a target of psychomotor stimulants, such as amphetamines and cocaine, and is a member of the sodium:neurotransmitter symporter family. A repeat length polymorphism in the promoter of this gene has been shown to affect the rate of serotonin uptake. There have been conflicting results in the literature about the possible effect, if any, that this polymorphism may play in behavior and depression. [provided by RefSeq, May 2019]

SLC6A4 links:

SLC6A4 (HGNC:):

SLC6A4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005604863).

BP6

Variant 17-30203175-T-G is Benign according to our data. Variant chr17-30203175-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 322529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00484 (738/152340) while in subpopulation EAS AF= 0.0331 (172/5190). AF 95% confidence interval is 0.0291. There are 12 homozygotes in gnomad4. There are 515 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 738 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A4	NM_001045.6 linkuse as main transcript	c.1815A>C	p.Lys605Asn	missense_variant	14/15	ENST00000650711.1	NP_001036.1	P31645-1B2R7Y7
LOC124903970	XR_007065699.1 linkuse as main transcript	n.174T>G		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A4	ENST00000650711.1 linkuse as main transcript	c.1815A>C	p.Lys605Asn	missense_variant	14/15		NM_001045.6	ENSP00000498537.1		P31645-1

Frequencies

GnomAD3 genomes

AF:

0.00485

AC:

738

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0329

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0437

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00128

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00665

AC:

1666

AN:

250632

Hom.:

AF XY:

0.00644

AC XY:

872

AN XY:

135450

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0304

Gnomad SAS exome

AF:

0.000687

Gnomad FIN exome

AF:

0.0411

Gnomad NFE exome

AF:

0.00144

Gnomad OTH exome

AF:

0.00540

GnomAD4 exome

AF:

0.00308

AC:

4499

AN:

1460478

Hom.:

Cov.:

AF XY:

0.00309

AC XY:

2242

AN XY:

726628

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0381

Gnomad4 SAS exome

AF:

0.000940

Gnomad4 FIN exome

AF:

0.0408

Gnomad4 NFE exome

AF:

0.000476

Gnomad4 OTH exome

AF:

0.00315

GnomAD4 genome

AF:

0.00484

AC:

738

AN:

152340

Hom.:

Cov.:

AF XY:

0.00691

AC XY:

515

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0331

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0437

Gnomad4 NFE

AF:

0.00128

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00159

Hom.:

Bravo

AF:

0.00157

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00618

AC:

750

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Behavior disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.73

D;D;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.64

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

.;D;D

MetaRNN

Benign

0.0056

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;L;.

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.7

D;D;.

REVEL

Benign

0.26

Sift

Benign

0.14

T;T;.

Sift4G

Benign

0.21

T;T;T

Polyphen

0.23

B;B;.

Vest4

0.59

MutPred

0.16

Loss of methylation at K605 (P = 4e-04);Loss of methylation at K605 (P = 4e-04);Loss of methylation at K605 (P = 4e-04);

MVP

0.28

MPC

1.2

ClinPred

0.078

GERP RS

-0.69

Varity_R

0.62

gMVP

0.89

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