chr16-55694046-T-C

Variant names:

• chr16-55694046-T-C
• rs1805068
• NM_001172501.3:c.955T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BS1 BS2

The NM_001172501.3(SLC6A2):​c.955T>C​(p.Leu319Leu) 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
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• postural orthostatic tachycardia syndrome

  Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2055 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001172501.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A2	NM_001172501.3	MANE Select	c.955T>C	p.Leu319Leu	synonymous	Exon 7 of 15	NP_001165972.1
	SLC6A2	NM_001172504.1		c.955T>C	p.Leu319Leu	synonymous	Exon 6 of 14	NP_001165975.1
	SLC6A2	NM_001043.3		c.955T>C	p.Leu319Leu	synonymous	Exon 6 of 14	NP_001034.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A2	ENST00000568943.6	TSL:1 MANE Select	c.955T>C	p.Leu319Leu	synonymous	Exon 7 of 15	ENSP00000457473.1
	SLC6A2	ENST00000379906.6	TSL:1	c.955T>C	p.Leu319Leu	synonymous	Exon 6 of 14	ENSP00000369237.2
	SLC6A2	ENST00000219833.13	TSL:5	c.955T>C	p.Leu319Leu	synonymous	Exon 6 of 14	ENSP00000219833.8

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

GnomAD2 exomes AF: 0.0134 AC: 3361 AN: 251478 AF XY: 0.0135

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 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

African (AFR) AF: 0.00320 AC: 107 AN: 33474

American (AMR) AF: 0.00367 AC: 164 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00608 AC: 159 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00333 AC: 287 AN: 86250

European-Finnish (FIN) AF: 0.0339 AC: 1810 AN: 53420

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.0212 AC: 23539 AN: 1111444

Other (OTH) AF: 0.0133 AC: 804 AN: 60376

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

African (AFR) AF: 0.00301 AC: 125 AN: 41564

American (AMR) AF: 0.00725 AC: 111 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4820

European-Finnish (FIN) AF: 0.0362 AC: 384 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0202 AC: 1371 AN: 68016

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.1
DANN	Benign	0.65
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1805068; hg19: chr16-55727958;