16-55671848-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001172501.3(SLC6A2):c.407-90T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,591,582 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Likely benign no assertion criteria provided B:2
• Conservation: PhyloP100: -0.193

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012292951).
• BP6: Variant 16-55671848-T-G is Benign according to our data. Variant chr16-55671848-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 1297547.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-55671848-T-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 268 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A2	NM_001172501.3	c.407-90T>G		intron_variant		ENST00000568943.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A2	ENST00000568943.6	c.407-90T>G		intron_variant		1	NM_001172501.3	P1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 152078 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00792

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00256

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00136 AC: 305 AN: 224036 Hom.: 1 AF XY: 0.00129 AC XY: 156 AN XY: 120812

Gnomad AFR exome AF: 0.000203

Gnomad AMR exome AF: 0.000279

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00624

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.000543

GnomAD4 exome AF: 0.00124 AC: 1778 AN: 1439386 Hom.: 3 Cov.: 31 AF XY: 0.00125 AC XY: 891 AN XY: 713134

Gnomad4 AFR exome AF: 0.000272

Gnomad4 AMR exome AF: 0.000234

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00618

Gnomad4 NFE exome AF: 0.00126

Gnomad4 OTH exome AF: 0.000960

GnomAD4 genome AF: 0.00175 AC: 267 AN: 152196 Hom.: 1 Cov.: 33 AF XY: 0.00194 AC XY: 144 AN XY: 74406

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00792

Gnomad4 NFE AF: 0.00254

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00308 Hom.: 1

Bravo AF: 0.000759

ExAC AF: 0.00140 AC: 170

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	0.062
Dann	Benign	0.69
FATHMM_MKL	Benign	0.022	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.012	T
MutationTaster	Benign	1.0	D;N;N;N;N;N;N
PROVEAN	Benign	-1.2	N
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.40
MVP		0.90
GERP RS		-3.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs552629380; hg19: chr16-55705760;