Genetic Variant NM_001172501.3:c.1369G>C (chr16-55698005-G-C) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

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

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.17

Publications

33 publications found

Variant links:

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

SLC6A2 links:

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ACMG classification

Classification was made for transcript

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

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

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.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurocirculatory asthenia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.42

MutationAssessor

Uncertain

2.9

PhyloP100

5.2

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.021

Polyphen

0.97

Vest4

0.80

MutPred

0.93

Loss of helix (P = 0.0626)

MVP

0.91

MPC

1.9

ClinPred

0.99

GERP RS

5.3

Varity_R

0.96

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over