rs6352

chr17-30203175-T-G

Variant summary

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

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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.852

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]

LOC124903970 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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 GnomAd at 738 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A4	NM_001045.6	c.1815A>C	p.Lys605Asn	missense_variant	14/15	ENST00000650711.1
LOC124903970	XR_007065699.1	n.174T>G		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A4	ENST00000650711.1	c.1815A>C	p.Lys605Asn	missense_variant	14/15		NM_001045.6	P1

Frequencies

GnomAD3 genomes AF: 0.00485 AC: 738 AN: 152222 Hom.: 12 Cov.: 33

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.: 29 AF XY: 0.00644 AC XY: 872 AN XY: 135450

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.: 81 Cov.: 29 AF XY: 0.00309 AC XY: 2242 AN XY: 726628

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.: 12 Cov.: 33 AF XY: 0.00691 AC XY: 515 AN XY: 74496

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.: 4

Bravo AF: 0.00157

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00618 AC: 750

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	20
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	D
MetaRNN	Benign	0.0056	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
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	T
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

Other links and lift over

dbSNP: rs6352; hg19: chr17-28530193; COSMIC: COSV55567087; COSMIC: COSV55567087;