chr16-55656715-C-A

Position:

chr16-55656715-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4_StrongBP6_ModerateBS2

The NM_001172501.3(SLC6A2):c.21C>A(p.Asn7Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000592 in 1,612,658 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00052 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 2 hom. )

Consequence

SLC6A2
NM_001172501.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0260

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SLC6A2. . Gene score misZ 2.0193 (greater than the threshold 3.09). Trascript score misZ 3.3305 (greater than threshold 3.09). GenCC has associacion of gene with postural orthostatic tachycardia syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.0108683705).

BP6

Variant 16-55656715-C-A is Benign according to our data. Variant chr16-55656715-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2057794.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A2	NM_001172501.3 linkuse as main transcript	c.21C>A	p.Asn7Lys	missense_variant	2/15	ENST00000568943.6	NP_001165972.1	P23975-1A0A024R6T9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A2	ENST00000568943.6 linkuse as main transcript	c.21C>A	p.Asn7Lys	missense_variant	2/15	1	NM_001172501.3	ENSP00000457473.1		P23975-1

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000620

AC:

153

AN:

246920

Hom.:

AF XY:

0.000722

AC XY:

AN XY:

134294

show subpopulations

Gnomad AFR exome

AF:

0.0000639

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00130

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.00103

Gnomad OTH exome

AF:

0.000658

GnomAD4 exome

AF:

0.000599

AC:

875

AN:

1460392

Hom.:

Cov.:

AF XY:

0.000617

AC XY:

448

AN XY:

726494

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.00126

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.000132

Gnomad4 NFE exome

AF:

0.000692

Gnomad4 OTH exome

AF:

0.000514

GnomAD4 genome

AF:

0.000519

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000853

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00116

Hom.:

Bravo

AF:

0.000521

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.000931

AC:

ExAC

AF:

0.000585

AC:

EpiCase

AF:

0.00147

EpiControl

AF:

0.00148

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.063

T;.;T;.;T;T;.;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.77

.;T;T;T;T;T;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.011

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.46

N;.;.;.;N;.;N;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.070

N;N;N;N;N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.78

T;T;T;T;T;T;T;T

Sift4G

Benign

0.57

T;T;T;T;T;T;T;T

Polyphen

0.0

B;.;.;.;B;.;.;.

Vest4

0.18

MutPred

0.15

Gain of ubiquitination at N7 (P = 0.0042);Gain of ubiquitination at N7 (P = 0.0042);Gain of ubiquitination at N7 (P = 0.0042);Gain of ubiquitination at N7 (P = 0.0042);Gain of ubiquitination at N7 (P = 0.0042);Gain of ubiquitination at N7 (P = 0.0042);Gain of ubiquitination at N7 (P = 0.0042);Gain of ubiquitination at N7 (P = 0.0042);

MVP

0.46

MPC

0.84

ClinPred

0.039

GERP RS

-1.4

Varity_R

0.063

gMVP

0.48

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