11-20601153-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004211.5(SLC6A5):c.28A>C(p.Asn10His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 33)
• Consequence: SLC6A5 NM_004211.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.90

Genes affected

SLC6A5 (HGNC:11051): (solute carrier family 6 member 5) This gene encodes a sodium- and chloride-dependent glycine neurotransmitter transporter. This integral membrane glycoprotein is responsible for the clearance of extracellular glycine during glycine-mediated neurotransmission. This protein is found in glycinergic axons and maintains a high presynaptic pool of neurotransmitter at glycinergic synapses. Mutations in this gene cause hyperekplexia; a heterogenous neurological disorder characterized by exaggerated startle responses and neonatal apnea. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19298437).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A5	NM_004211.5	c.28A>C	p.Asn10His	missense_variant	2/16	ENST00000525748.6
SLC6A5	NM_001318369.2	c.-536A>C		5_prime_UTR_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A5	ENST00000525748.6	c.28A>C	p.Asn10His	missense_variant	2/16	1	NM_004211.5	P1
SLC6A5	ENST00000298923.11	c.28A>C	p.Asn10His	missense_variant, NMD_transcript_variant	2/15	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperekplexia 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2022

This variant has not been reported in the literature in individuals affected with SLC6A5-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC6A5 protein function. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 10 of the SLC6A5 protein (p.Asn10His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.042
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.89	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.26
Sift	Uncertain	0.010	D
Sift4G	Benign	0.071	T
Polyphen		0.21	B
Vest4		0.36
MutPred		0.052		Gain of glycosylation at K7 (P = 0.1125);
MVP		0.83
MPC		0.31
ClinPred		0.65	D
GERP RS		5.7
Varity_R		0.17
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr11-20622699;