16-55656715-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0260

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 -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SLC6A2
• 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 GnomAd at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A2	NM_001172501.3	c.21C>A	p.Asn7Lys	missense_variant	2/15	ENST00000568943.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A2	ENST00000568943.6	c.21C>A	p.Asn7Lys	missense_variant	2/15	1	NM_001172501.3	P1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152148 Hom.: 0 Cov.: 32

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.: 1 AF XY: 0.000722 AC XY: 97 AN XY: 134294

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.: 2 Cov.: 32 AF XY: 0.000617 AC XY: 448 AN XY: 726494

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: 79 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74432

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.: 0

Bravo AF: 0.000521

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.000585 AC: 71

EpiCase AF: 0.00147

EpiControl AF: 0.00148

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	15
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	N
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.46	N;.;.;.;N;.;N;.
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.070	N;N;N;N;N;N;N;N
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	T
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

Other links and lift over

dbSNP: rs11568323; hg19: chr16-55690627;