rs1805066

chr16-55685231-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001172501.3(SLC6A2):c.733G>A(p.Val245Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00879 in 1,614,014 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0060 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0091 (73 hom.)
• Consequence: SLC6A2 NM_001172501.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.26

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SLC6A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0048825443).
• BP6: Variant 16-55685231-G-A is Benign according to our data. Variant chr16-55685231-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 769421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 921 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A2	NM_001172501.3	c.733G>A	p.Val245Ile	missense_variant	5/15	ENST00000568943.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A2	ENST00000568943.6	c.733G>A	p.Val245Ile	missense_variant	5/15	1	NM_001172501.3	P1

Frequencies

GnomAD3 genomes AF: 0.00605 AC: 921 AN: 152196 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00819

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00607 AC: 1525 AN: 251440 Hom.: 3 AF XY: 0.00603 AC XY: 819 AN XY: 135886

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.000652

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.00905

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.00799

GnomAD4 exome AF: 0.00908 AC: 13273 AN: 1461700 Hom.: 73 Cov.: 32 AF XY: 0.00880 AC XY: 6400 AN XY: 727154

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00161

Gnomad4 FIN exome AF: 0.0107

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.00757

GnomAD4 genome AF: 0.00604 AC: 920 AN: 152314 Hom.: 4 Cov.: 33 AF XY: 0.00564 AC XY: 420 AN XY: 74476

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00819

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00840 Hom.: 7

Bravo AF: 0.00534

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00907 AC: 78

ExAC AF: 0.00609 AC: 739

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	SLC6A2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

SLC6A2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 07, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	16
Dann	Benign	0.93
DEOGEN2	Benign	0.090	T;.;T;T;T;.;T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.74	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0049	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.72	N;.;.;N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.47	N;N;N;N;N;N;N;N
Sift	Benign	0.42	T;T;T;T;T;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;B;.;.;.;.
Vest4		0.21
MVP		0.64
MPC		0.59
ClinPred		0.0021	T
GERP RS		3.3
Varity_R		0.037
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1805066; hg19: chr16-55719143; COSMIC: COSV54924729;