rs61736602

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004211.5(SLC6A5):c.266C>A(p.Ala89Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0278 in 1,603,806 control chromosomes in the GnomAD database, including 739 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A89A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.022 ( 43 hom., cov: 33)

Exomes 𝑓: 0.028 ( 696 hom. )

Consequence

SLC6A5
NM_004211.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.905

Publications

11 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, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia
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=0.0025437474).

BP6

Variant 11-20601391-C-A is Benign according to our data. Variant chr11-20601391-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 304001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0215 (3280/152332) while in subpopulation NFE AF = 0.0332 (2259/68012). AF 95% confidence interval is 0.0321. There are 43 homozygotes in GnomAd4. There are 1553 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 43 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004211.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A5	NM_004211.5	MANE Select	c.266C>A	p.Ala89Glu	missense	Exon 2 of 16	NP_004202.4	Q9Y345-1
	SLC6A5	NM_001318369.2		c.-298C>A		5_prime_UTR	Exon 2 of 15	NP_001305298.1	Q9Y345-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A5	ENST00000525748.6	TSL:1 MANE Select	c.266C>A	p.Ala89Glu	missense	Exon 2 of 16	ENSP00000434364.2	Q9Y345-1
	SLC6A5	ENST00000298923.11	TSL:1	n.266C>A		non_coding_transcript_exon	Exon 2 of 15	ENSP00000298923.7	J3KNC4

Frequencies

GnomAD3 genomes

AF:

0.0216

AC:

3282

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00612

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0199

Gnomad ASJ

AF:

0.0230

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.0261

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0332

Gnomad OTH

AF:

0.0292

GnomAD2 exomes

AF:

0.0208

AC:

4627

AN:

221962

AF XY:

0.0212

show subpopulations

Gnomad AFR exome

AF:

0.00452

Gnomad AMR exome

AF:

0.0134

Gnomad ASJ exome

AF:

0.0259

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0261

Gnomad NFE exome

AF:

0.0316

Gnomad OTH exome

AF:

0.0247

GnomAD4 exome

AF:

0.0285

AC:

41297

AN:

1451474

Hom.:

696

Cov.:

AF XY:

0.0280

AC XY:

20192

AN XY:

721464

show subpopulations

African (AFR)

AF:

0.00513

AC:

171

AN:

33326

American (AMR)

AF:

0.0140

AC:

609

AN:

43510

Ashkenazi Jewish (ASJ)

AF:

0.0262

AC:

679

AN:

25876

East Asian (EAS)

AF:

0.0000510

AC:

AN:

39240

South Asian (SAS)

AF:

0.00673

AC:

572

AN:

84994

European-Finnish (FIN)

AF:

0.0276

AC:

1402

AN:

50760

Middle Eastern (MID)

AF:

0.0181

AC:

103

AN:

5698

European-Non Finnish (NFE)

AF:

0.0327

AC:

36271

AN:

1108126

Other (OTH)

AF:

0.0248

AC:

1488

AN:

59944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

2601

5202

7802

10403

13004

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1314

2628

3942

5256

6570

<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:

0.0215

AC:

3280

AN:

152332

Hom.:

Cov.:

AF XY:

0.0208

AC XY:

1553

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00613

AC:

255

AN:

41592

American (AMR)

AF:

0.0198

AC:

303

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0230

AC:

AN:

3472

East Asian (EAS)

AF:

0.000772

AC:

AN:

5178

South Asian (SAS)

AF:

0.00559

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0261

AC:

277

AN:

10626

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0332

AC:

2259

AN:

68012

Other (OTH)

AF:

0.0289

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

157

315

472

630

787

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0284

Hom.:

117

Bravo

AF:

0.0202

TwinsUK

AF:

0.0383

AC:

142

ALSPAC

AF:

0.0335

AC:

129

ESP6500AA

AF:

0.00665

AC:

ESP6500EA

AF:

0.0322

AC:

274

ExAC

AF:

0.0197

AC:

2369

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyperekplexia 3 (3)

Hyperekplexia (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.033

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.1

PhyloP100

0.91

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.26

REVEL

Benign

0.13

Sift

Uncertain

0.024

Sift4G

Benign

0.13

Polyphen

0.089

Vest4

0.13

MPC

0.26

ClinPred

0.0065

GERP RS

1.9

Varity_R

0.21

gMVP

0.49

Mutation Taster

=96/4

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over