NM_004211.5:c.2299G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 9.54

Publications

18 publications found

Variant links:

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]

SLC6A5 Gene-Disease associations (from GenCC):

hyperekplexia 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
hereditary hyperekplexia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SLC6A5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 304040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
SLC6A5	NM_004211.5 link	c.2299G>A	p.Gly767Arg	missense_variant	Exon 16 of 16	ENST00000525748.6	NP_004202.4	Q9Y345-1Q4VAM4Q4VAM6
SLC6A5	NM_001318369.2 link	c.1597G>A	p.Gly533Arg	missense_variant	Exon 15 of 15		NP_001305298.1	Q9Y345-2Q4VAM4
SLC6A5	XM_017018544.3 link	c.1423G>A	p.Gly475Arg	missense_variant	Exon 12 of 12		XP_016874033.1
SLC6A5	XR_007062528.1 link	n.1677G>A		non_coding_transcript_exon_variant	Exon 13 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC6A5	ENST00000525748.6 link	c.2299G>A	p.Gly767Arg	missense_variant	Exon 16 of 16	1	NM_004211.5	ENSP00000434364.2	Q9Y345-1
SLC6A5	ENST00000298923.11 link	n.*1596G>A		non_coding_transcript_exon_variant	Exon 15 of 15	1		ENSP00000298923.7	J3KNC4
SLC6A5	ENST00000298923.11 link	n.*1596G>A		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000298923.7	J3KNC4
SLC6A5	ENST00000528440.1 link	n.830G>A		non_coding_transcript_exon_variant	Exon 8 of 8	5

Frequencies

GnomAD3 genomes

AF:

0.0147

AC:

2243

AN:

152104

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0214

AC:

5390

AN:

251484

AF XY:

0.0191

show subpopulations

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 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.:

AF XY:

0.0117

AC XY:

8538

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00714

AC:

239

AN:

33480

American (AMR)

AF:

0.0871

AC:

3896

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0103

AC:

268

AN:

26136

East Asian (EAS)

AF:

0.0123

AC:

490

AN:

39700

South Asian (SAS)

AF:

0.0218

AC:

1883

AN:

86256

European-Finnish (FIN)

AF:

0.00193

AC:

103

AN:

53420

Middle Eastern (MID)

AF:

0.00693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00884

AC:

9830

AN:

1111972

Other (OTH)

AF:

0.0111

AC:

673

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1068

2135

3203

4270

5338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

434

868

1302

1736

2170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0147

AC:

2243

AN:

152222

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

1215

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00782

AC:

325

AN:

41546

American (AMR)

AF:

0.0689

AC:

1052

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00952

AC:

AN:

3466

East Asian (EAS)

AF:

0.0162

AC:

AN:

5172

South Asian (SAS)

AF:

0.0210

AC:

101

AN:

4818

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00906

AC:

616

AN:

68014

Other (OTH)

AF:

0.00853

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

108

216

323

431

539

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0107

Hom.:

Bravo

AF:

0.0179

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.00895

AC:

ExAC

AF:

0.0174

AC:

2109

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.00823

EpiControl

AF:

0.00717

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperekplexia 3

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hyperekplexia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.032

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0052

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.6

PhyloP100

9.5

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.47

Sift

Benign

0.12

Sift4G

Benign

0.19

Polyphen

0.95

Vest4

0.28

MutPred

0.52

Loss of ubiquitination at K771 (P = 0.0328);

MPC

0.39

ClinPred

0.033

GERP RS

5.9

Varity_R

0.33

gMVP

0.88

Mutation Taster

=74/26

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over