NM_001045.6:c.-220-1732C>T

Variant names:

• chr17-30224647-G-A
• rs2066713
• NM_001045.6:c.-220-1732C>T

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_001045.6(SLC6A4):c.-220-1732C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.338 (AC=51,358) in the gnomAD database across 152,060 control chromosomes, including 9,252 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.389. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.34 (9252 hom., cov: 32)
• Consequence: SLC6A4 NM_001045.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.966
• Publications: 64 publications found

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 Gene-Disease associations (from GenCC):

• obsessive-compulsive disorder

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia
• autism spectrum disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.3892 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001045.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SLC6A4 NM_001045.6	MANE Select	c.-220-1732C>T	intron	Intron 1 of 14	Prot: NP_001036.1 UniProt:

SLC6A4 NM_001045.6

MANE Select

HGVSc / HGVSpc.-220-1732C>T

Exon rankIntron 1 of 14

intron

Prot: NP_001036.1UniProt: P31645-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SLC6A4 ENST00000650711.1	MANE Select	c.-220-1732C>T	intron	Intron 1 of 14	Prot: ENSP00000498537.1 UniProt:
	SLC6A4 ENST00000261707.7	TSL:1	c.-220-1732C>T	intron	Intron 1 of 14	Prot: ENSP00000261707.3 UniProt:
	SLC6A4 ENST00000394821.2	TSL:1	c.-220-1732C>T	intron	Intron 1 of 14	Prot: ENSP00000378298.2 UniProt:

SLC6A4 ENST00000650711.1

MANE Select

HGVSc / HGVSpc.-220-1732C>T

Exon rankIntron 1 of 14

intron

Prot: ENSP00000498537.1UniProt: P31645-1

SLC6A4 ENST00000261707.7

TSL:1

HGVSc / HGVSpc.-220-1732C>T

Exon rankIntron 1 of 14

intron

Prot: ENSP00000261707.3UniProt: P31645-1

SLC6A4 ENST00000394821.2

TSL:1

HGVSc / HGVSpc.-220-1732C>T

Exon rankIntron 1 of 14

intron

Prot: ENSP00000378298.2UniProt: J3KPR9

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.338	AC:51314	Hom:9236	AN:151942	Cov:32
GnomAD4 genome	AF: 0.338	AC:51358	Hom:9252	AN:152060	Cov:32
TOPMed (Bravo)	AF: 0.323	AC:85563	Hom:14714	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.366	AC:245459	Hom:45928	AN:670578	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.341	AC:799	Hom:153	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0757	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.473	AC:142	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.235	AC:817	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.0700	AC:509	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.375	AC:66	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0720	AC:8837	Hom:326	AN:122674	Cov:
Turkish Variome	AF: 0.291	AC:450	Hom:71	AN:1546	Cov:
UK10K	AF: 0.399	AC:3014	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.0883	AC:791	Hom:39	AN:8960	Cov:

Showing 14 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	6.5
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.72
DANN	Benign	0.51
GPN-Star LLR	N/A	0.041
GPN-Star score	N/A	-0.041
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-0.97

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs2066713;

hg19: chr17-28551665;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar