chr16-55679176-C-T

Variant names:

• chr16-55679176-C-T
• rs36020
• NM_001172501.3:c.645-5967C>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_001172501.3(SLC6A2):c.645-5967C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.114 (AC=17,255) in the gnomAD database across 151,980 control chromosomes, including 1,082 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.159. 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 0.11 (1082 hom., cov: 32)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.28
• Publications: 8 publications found

Genes affected

SLC6A2 (HGNC:11048): (solute carrier family 6 member 2) This gene encodes a member of the sodium:neurotransmitter symporter family. This member is a multi-pass membrane protein, which is responsible for reuptake of norepinephrine into presynaptic nerve terminals and is a regulator of norepinephrine homeostasis. Mutations in this gene cause orthostatic intolerance, a syndrome characterized by lightheadedness, fatigue, altered mentation and syncope. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene.[provided by RefSeq, Feb 2010]

SLC6A2 Gene-Disease associations (from GenCC):

• postural orthostatic tachycardia syndrome due to NET deficiency

  Inheritance: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

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 = 0.1586 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001172501.3. 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
	SLC6A2	NM_001172501.3	MANE Select	c.645-5967C>T		intron	N/A	NP_001165972.1	P23975-1
	SLC6A2	NM_001172504.1		c.645-5967C>T		intron	N/A	NP_001165975.1	P23975-2
	SLC6A2	NM_001043.3		c.645-5967C>T		intron	N/A	NP_001034.1	P23975-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A2	ENST00000568943.6	TSL:1 MANE Select	c.645-5967C>T		intron	N/A	ENSP00000457473.1	P23975-1
	SLC6A2	ENST00000379906.6	TSL:1	c.645-5967C>T		intron	N/A	ENSP00000369237.2	P23975-1
	SLC6A2	ENST00000219833.13	TSL:5	c.645-5967C>T		intron	N/A	ENSP00000219833.8	P23975-2

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: 0.114	AC:17241	Hom:1078	AN:151886	Cov:32
GnomAD4 genome	AF: 0.114	AC:17255	Hom:1082	AN:151980	Cov:32
TOPMed (Bravo)	AF: 0.107	AC:28371	Hom:1688	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.125	AC:30731	Hom:2029	AN:244988	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.128	AC:300	Hom:18	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.175	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.127	AC:38	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.130	AC:452	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.166	AC:1201	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.0909	AC:16	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.162	AC:19847	Hom:1594	AN:122456	Cov:
Turkish Variome	AF: 0.106	AC:164	Hom:14	AN:1546	Cov:
UK10K	AF: 0.147	AC:1109	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.181	AC:1622	Hom:154	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	0.53
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.075
DANN	Benign	0.21
GPN-Star LLR	N/A	2.2
GPN-Star score	N/A	1.8
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-3.3

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.

Other links and lift over

dbSNP: rs36020;

hg19: chr16-55713088;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar