16-55656781-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001172501.3(SLC6A2):c.87A>C(p.Lys29Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K29R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A2 NM_001172501.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.673

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SLC6A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.2607504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A2	NM_001172501.3	c.87A>C	p.Lys29Asn	missense_variant	2/15	ENST00000568943.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A2	ENST00000568943.6	c.87A>C	p.Lys29Asn	missense_variant	2/15	1	NM_001172501.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2023

The c.87A>C (p.K29N) alteration is located in exon 1 (coding exon 1) of the SLC6A2 gene. This alteration results from a A to C substitution at nucleotide position 87, causing the lysine (K) at amino acid position 29 to be replaced by an asparagine (N). 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	0.29
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	21
Dann	Benign	0.88
DEOGEN2	Benign	0.10	T;.;T;.;T;T;.;T
Eigen	Benign	0.054
Eigen_PC	Benign	0.019
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.9	L;.;.;.;L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N
Sift	Uncertain	0.017	D;T;D;D;D;D;D;D
Sift4G	Uncertain	0.060	T;D;D;T;T;T;T;T
Polyphen		0.99	D;.;.;.;D;.;.;.
Vest4		0.24
MutPred		0.24		Loss of ubiquitination at K29 (P = 0.0098);Loss of ubiquitination at K29 (P = 0.0098);Loss of ubiquitination at K29 (P = 0.0098);Loss of ubiquitination at K29 (P = 0.0098);Loss of ubiquitination at K29 (P = 0.0098);Loss of ubiquitination at K29 (P = 0.0098);Loss of ubiquitination at K29 (P = 0.0098);Loss of ubiquitination at K29 (P = 0.0098);
MVP		0.79
MPC		1.6
ClinPred		0.78	D
GERP RS		3.0
Varity_R		0.15
gMVP		0.60

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.

Other links and lift over

hg19: chr16-55690693;