chr16-55698034-G-A

Variant names:

• chr16-55698034-G-A
• rs998424
• NM_001172501.3:c.1389+9G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001172501.3(SLC6A2):​c.1389+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 1,613,250 control chromosomes in the GnomAD database, including 88,058 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6229 hom., cov: 32)
  • Exomes 𝑓: 0.33 (81829 hom.)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.80
• Publications: 32 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 16-55698034-G-A is Benign according to our data. Variant chr16-55698034-G-A is described in ClinVar as Benign. ClinVar VariationId is 1282997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

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.1389+9G>A		intron	N/A	NP_001165972.1
	SLC6A2	NM_001172504.1		c.1389+9G>A		intron	N/A	NP_001165975.1
	SLC6A2	NM_001043.3		c.1389+9G>A		intron	N/A	NP_001034.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A2	ENST00000568943.6	TSL:1 MANE Select	c.1389+9G>A		intron	N/A	ENSP00000457473.1
	SLC6A2	ENST00000379906.6	TSL:1	c.1389+9G>A		intron	N/A	ENSP00000369237.2
	SLC6A2	ENST00000219833.13	TSL:5	c.1389+9G>A		intron	N/A	ENSP00000219833.8

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40362 AN: 151954 Hom.: 6224 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.375

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.260

GnomAD2 exomes AF: 0.312 AC: 78458 AN: 251348 AF XY: 0.307

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.414

Gnomad ASJ exome AF: 0.275

Gnomad EAS exome AF: 0.295

Gnomad FIN exome AF: 0.348

Gnomad NFE exome AF: 0.341

Gnomad OTH exome AF: 0.291

GnomAD4 exome AF: 0.329 AC: 480022 AN: 1461176 Hom.: 81829 Cov.: 37 AF XY: 0.324 AC XY: 235852 AN XY: 726920

African (AFR) AF: 0.0968 AC: 3241 AN: 33470

American (AMR) AF: 0.401 AC: 17946 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 7275 AN: 26134

East Asian (EAS) AF: 0.265 AC: 10534 AN: 39696

South Asian (SAS) AF: 0.201 AC: 17373 AN: 86244

European-Finnish (FIN) AF: 0.344 AC: 18364 AN: 53408

Middle Eastern (MID) AF: 0.242 AC: 1393 AN: 5768

European-Non Finnish (NFE) AF: 0.347 AC: 385751 AN: 1111362

Other (OTH) AF: 0.301 AC: 18145 AN: 60372

GnomAD4 genome AF: 0.265 AC: 40371 AN: 152074 Hom.: 6229 Cov.: 32 AF XY: 0.267 AC XY: 19839 AN XY: 74318

African (AFR) AF: 0.111 AC: 4586 AN: 41490

American (AMR) AF: 0.331 AC: 5065 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 932 AN: 3466

East Asian (EAS) AF: 0.276 AC: 1424 AN: 5154

South Asian (SAS) AF: 0.192 AC: 920 AN: 4804

European-Finnish (FIN) AF: 0.353 AC: 3740 AN: 10584

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.334 AC: 22732 AN: 67968

Other (OTH) AF: 0.257 AC: 543 AN: 2114

Alfa AF: 0.286 Hom.: 3879

Bravo AF: 0.259

Asia WGS AF: 0.206 AC: 718 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 28, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.7
DANN	Benign	0.76
PhyloP100		1.8
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: rs998424; hg19: chr16-55731946; COSMIC: COSV54912981; COSMIC: COSV54912981;