Variant chr16-55656848-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001172501.3(SLC6A2):c.154G>T(p.Asp52Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SLC6A2
NM_001172501.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.22

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27224696).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A2	NM_001172501.3 link	c.154G>T	p.Asp52Tyr	missense_variant	2/15	ENST00000568943.6	NP_001165972.1	P23975-1A0A024R6T9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A2	ENST00000568943.6 link	c.154G>T	p.Asp52Tyr	missense_variant	2/15	1	NM_001172501.3	ENSP00000457473.1		P23975-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461458

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727050

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2024

The c.154G>T (p.D52Y) alteration is located in exon 1 (coding exon 1) of the SLC6A2 gene. This alteration results from a G to T substitution at nucleotide position 154, causing the aspartic acid (D) at amino acid position 52 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.000080

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Benign

0.33

T;.;T;.;T;T;.;T

Eigen

Benign

-0.039

Eigen_PC

Benign

0.011

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.88

.;D;D;D;D;D;D;D

M_CAP

Benign

0.067

MetaRNN

Benign

0.27

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.2

L;.;.;.;L;.;L;.

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.7

D;N;D;N;D;D;D;N

REVEL

Benign

0.24

Sift

Uncertain

0.0080

D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.011

D;D;D;D;D;D;D;D

Polyphen

0.56

P;.;.;.;P;.;.;.

Vest4

0.33

MutPred

0.39

Loss of disorder (P = 0.0219);Loss of disorder (P = 0.0219);Loss of disorder (P = 0.0219);Loss of disorder (P = 0.0219);Loss of disorder (P = 0.0219);Loss of disorder (P = 0.0219);Loss of disorder (P = 0.0219);Loss of disorder (P = 0.0219);

MVP

0.83

MPC

1.5

ClinPred

0.95

GERP RS

5.3

Varity_R

0.31

gMVP

0.55

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over