rs16906628

chr11-20654773-G-Achr11-20654773-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004211.5(SLC6A5):c.2299G>A(p.Gly767Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,614,068 control chromosomes in the GnomAD database, including 363 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G767E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (64 hom., cov: 32)
  • Exomes 𝑓: 0.012 (299 hom.)
• Consequence: SLC6A5 NM_004211.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.54

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00515756).
• BP6: Variant 11-20654773-G-A is Benign according to our data. Variant chr11-20654773-G-A is described in ClinVar as [Benign]. Clinvar id is 304040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-20654773-G-A is described in Lovd as [Likely_benign]. Variant chr11-20654773-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A5	NM_004211.5	c.2299G>A	p.Gly767Arg	missense_variant	16/16	ENST00000525748.6
SLC6A5	NM_001318369.2	c.1597G>A	p.Gly533Arg	missense_variant	15/15
SLC6A5	XM_017018544.3	c.1423G>A	p.Gly475Arg	missense_variant	12/12
SLC6A5	XR_007062528.1	n.1677G>A		non_coding_transcript_exon_variant	13/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A5	ENST00000525748.6	c.2299G>A	p.Gly767Arg	missense_variant	16/16	1	NM_004211.5	P1
SLC6A5	ENST00000298923.11	c.*1596G>A		3_prime_UTR_variant, NMD_transcript_variant	15/15	1
SLC6A5	ENST00000528440.1	n.830G>A		non_coding_transcript_exon_variant	8/8	5

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2243 AN: 152104 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.00787

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0691

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.0160

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00906

Gnomad OTH AF: 0.00862

GnomAD3 exomes AF: 0.0214 AC: 5390 AN: 251484 Hom.: 181 AF XY: 0.0191 AC XY: 2596 AN XY: 135920

Gnomad AFR exome AF: 0.00695

Gnomad AMR exome AF: 0.0910

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.0178

Gnomad SAS exome AF: 0.0218

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00804

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0119 AC: 17422 AN: 1461846 Hom.: 299 Cov.: 32 AF XY: 0.0117 AC XY: 8538 AN XY: 727234

Gnomad4 AFR exome AF: 0.00714

Gnomad4 AMR exome AF: 0.0871

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.0123

Gnomad4 SAS exome AF: 0.0218

Gnomad4 FIN exome AF: 0.00193

Gnomad4 NFE exome AF: 0.00884

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.0147 AC: 2243 AN: 152222 Hom.: 64 Cov.: 32 AF XY: 0.0163 AC XY: 1215 AN XY: 74436

Gnomad4 AFR AF: 0.00782

Gnomad4 AMR AF: 0.0689

Gnomad4 ASJ AF: 0.00952

Gnomad4 EAS AF: 0.0162

Gnomad4 SAS AF: 0.0210

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00906

Gnomad4 OTH AF: 0.00853

Alfa AF: 0.0101 Hom.: 45

Bravo AF: 0.0179

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.00895 AC: 77

ExAC AF: 0.0174 AC: 2109

Asia WGS AF: 0.0180 AC: 63 AN: 3478

EpiCase AF: 0.00823

EpiControl AF: 0.00717

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperekplexia 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hyperekplexia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.032	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.47
Sift	Benign	0.12	T
Sift4G	Benign	0.19	T
Polyphen		0.95	P
Vest4		0.28
MutPred		0.52		Loss of ubiquitination at K771 (P = 0.0328);
MPC		0.39
ClinPred		0.033	T
GERP RS		5.9
Varity_R		0.33
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs16906628; hg19: chr11-20676319; COSMIC: COSV54230001;