16-55669586-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001172501.3(SLC6A2):c.296C>T(p.Thr99Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,613,980 control chromosomes in the GnomAD database, including 287 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.011 (13 hom., cov: 32)
  • Exomes 𝑓: 0.017 (274 hom.)
• Consequence: SLC6A2 NM_001172501.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.25

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SLC6A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0070825815).
• BP6: Variant 16-55669586-C-T is Benign according to our data. Variant chr16-55669586-C-T is described in ClinVar as [Benign]. Clinvar id is 778123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0106 (1621/152300) while in subpopulation NFE AF= 0.0173 (1176/68024). AF 95% confidence interval is 0.0165. There are 13 homozygotes in gnomad4. There are 758 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1621 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A2	NM_001172501.3	c.296C>T	p.Thr99Ile	missense_variant	3/15	ENST00000568943.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A2	ENST00000568943.6	c.296C>T	p.Thr99Ile	missense_variant	3/15	1	NM_001172501.3	P1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1621 AN: 152182 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00950 AC: 2388 AN: 251340 Hom.: 25 AF XY: 0.00953 AC XY: 1295 AN XY: 135840

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00804

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00457

Gnomad FIN exome AF: 0.00231

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0172 AC: 25156 AN: 1461680 Hom.: 274 Cov.: 32 AF XY: 0.0167 AC XY: 12170 AN XY: 727158

Gnomad4 AFR exome AF: 0.00233

Gnomad4 AMR exome AF: 0.00586

Gnomad4 ASJ exome AF: 0.00719

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00448

Gnomad4 FIN exome AF: 0.00271

Gnomad4 NFE exome AF: 0.0207

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0106 AC: 1621 AN: 152300 Hom.: 13 Cov.: 32 AF XY: 0.0102 AC XY: 758 AN XY: 74464

Gnomad4 AFR AF: 0.00354

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.00348

Gnomad4 NFE AF: 0.0173

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0149 Hom.: 21

Bravo AF: 0.0113

TwinsUK AF: 0.0170 AC: 63

ALSPAC AF: 0.0197 AC: 76

ESP6500AA AF: 0.00478 AC: 21

ESP6500EA AF: 0.0184 AC: 158

ExAC AF: 0.00937 AC: 1137

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0189

EpiControl AF: 0.0145

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

SLC6A2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 27, 2019

This variant is classified as 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	0.086
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	19
Dann	Benign	0.90
DEOGEN2	Benign	0.051	T;.;T;.;T;T;.;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.44	N
MetaRNN	Benign	0.0071	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.53	N;.;.;.;N;.;N;.
MutationTaster	Benign	0.68	D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.060	N;N;N;N;N;N;N;N
Sift	Benign	0.78	T;T;T;T;T;T;T;T
Sift4G	Benign	0.43	T;T;T;T;T;T;T;T
Polyphen		0.0010	B;.;.;.;B;.;.;.
Vest4		0.19
MVP		0.70
MPC		0.79
ClinPred		0.0085	T
GERP RS		4.9
Varity_R		0.084
gMVP		0.29

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: rs1805065; hg19: chr16-55703498; COSMIC: COSV54920340; COSMIC: COSV54920340;