rs1805068

chr16-55694046-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BS1 BS2

The NM_001172501.3(SLC6A2):c.955T>C(p.Leu319=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,613,572 control chromosomes in the GnomAD database, including 356 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.013 (32 hom., cov: 33)
  • Exomes 𝑓: 0.018 (324 hom.)
• Consequence: SLC6A2 NM_001172501.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.225

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP7: Synonymous conserved (PhyloP=0.225 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0135 (2055/152286) while in subpopulation NFE AF= 0.0202 (1371/68016). AF 95% confidence interval is 0.0193. There are 32 homozygotes in gnomad4. There are 1081 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2054 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A2	NM_001172501.3	c.955T>C	p.Leu319=	synonymous_variant	7/15	ENST00000568943.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A2	ENST00000568943.6	c.955T>C	p.Leu319=	synonymous_variant	7/15	1	NM_001172501.3	P1

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2054 AN: 152168 Hom.: 32 Cov.: 33

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00726

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0362

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0134 AC: 3361 AN: 251478 Hom.: 54 AF XY: 0.0135 AC XY: 1835 AN XY: 135910

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.00625

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00346

Gnomad FIN exome AF: 0.0344

Gnomad NFE exome AF: 0.0194

Gnomad OTH exome AF: 0.00961

GnomAD4 exome AF: 0.0184 AC: 26885 AN: 1461286 Hom.: 324 Cov.: 30 AF XY: 0.0180 AC XY: 13079 AN XY: 727016

Gnomad4 AFR exome AF: 0.00320

Gnomad4 AMR exome AF: 0.00367

Gnomad4 ASJ exome AF: 0.00608

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00333

Gnomad4 FIN exome AF: 0.0339

Gnomad4 NFE exome AF: 0.0212

Gnomad4 OTH exome AF: 0.0133

GnomAD4 genome AF: 0.0135 AC: 2055 AN: 152286 Hom.: 32 Cov.: 33 AF XY: 0.0145 AC XY: 1081 AN XY: 74456

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.00725

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0362

Gnomad4 NFE AF: 0.0202

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0160 Hom.: 10

Bravo AF: 0.0111

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0149

EpiControl AF: 0.0171

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	5.1
Dann	Benign	0.65

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: rs1805068; hg19: chr16-55727958;