16-55698005-G-C

Variant names:

• chr16-55698005-G-C
• rs121918126
• NM_001172501.3:c.1369G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001172501.3(SLC6A2):​c.1369G>C​(p.Ala457Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A2 NM_001172501.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.17
• Publications: 34 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: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 16-55698005-G-C is Pathogenic according to our data. Variant chr16-55698005-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 14006.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A2	NM_001172501.3	MANE Select	c.1369G>C	p.Ala457Pro	missense	Exon 10 of 15	NP_001165972.1	P23975-1
	SLC6A2	NM_001172504.1		c.1369G>C	p.Ala457Pro	missense	Exon 9 of 14	NP_001165975.1	P23975-2
	SLC6A2	NM_001043.3		c.1369G>C	p.Ala457Pro	missense	Exon 9 of 14	NP_001034.1	P23975-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A2	ENST00000568943.6	TSL:1 MANE Select	c.1369G>C	p.Ala457Pro	missense	Exon 10 of 15	ENSP00000457473.1	P23975-1
	SLC6A2	ENST00000379906.6	TSL:1	c.1369G>C	p.Ala457Pro	missense	Exon 9 of 14	ENSP00000369237.2	P23975-1
	SLC6A2	ENST00000219833.13	TSL:5	c.1369G>C	p.Ala457Pro	missense	Exon 9 of 14	ENSP00000219833.8	P23975-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neurocirculatory asthenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
PhyloP100		5.2
Varity_R		0.96
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121918126; hg19: chr16-55731917;