11-20601262-C-G

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.137C>G(p.Pro46Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 1,583,946 control chromosomes in the GnomAD database, including 40 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0062 ( 37 hom. )

Consequence

SLC6A5
NM_004211.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.635

Publications

2 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=0.006926596).

BP6

Variant 11-20601262-C-G is Benign according to our data. Variant chr11-20601262-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 303999.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 = 0.00462 (703/152308) while in subpopulation NFE AF = 0.00726 (494/68018). AF 95% confidence interval is 0.00673. There are 3 homozygotes in GnomAd4. There are 318 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A5	NM_004211.5 link	c.137C>G	p.Pro46Arg	missense_variant	Exon 2 of 16	ENST00000525748.6	NP_004202.4	Q9Y345-1Q4VAM4Q4VAM6
SLC6A5	NM_001318369.2 link	c.-427C>G		5_prime_UTR_variant	Exon 2 of 15		NP_001305298.1	Q9Y345-2Q4VAM4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A5	ENST00000525748.6 link	c.137C>G	p.Pro46Arg	missense_variant	Exon 2 of 16	1	NM_004211.5	ENSP00000434364.2		Q9Y345-1
SLC6A5	ENST00000298923.11 link	n.137C>G		non_coding_transcript_exon_variant	Exon 2 of 15	1		ENSP00000298923.7		J3KNC4

Frequencies

GnomAD3 genomes

AF:

0.00463

AC:

705

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00504

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00668

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00728

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00427

AC:

834

AN:

195416

AF XY:

0.00438

show subpopulations

Gnomad AFR exome

AF:

0.00120

Gnomad AMR exome

AF:

0.00219

Gnomad ASJ exome

AF:

0.000112

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00634

Gnomad NFE exome

AF:

0.00760

Gnomad OTH exome

AF:

0.00534

GnomAD4 exome

AF:

0.00623

AC:

8924

AN:

1431638

Hom.:

Cov.:

AF XY:

0.00595

AC XY:

4231

AN XY:

710788

show subpopulations

African (AFR)

AF:

0.00124

AC:

AN:

33180

American (AMR)

AF:

0.00226

AC:

AN:

42570

Ashkenazi Jewish (ASJ)

AF:

0.0000778

AC:

AN:

25692

East Asian (EAS)

AF:

0.00

AC:

AN:

38952

South Asian (SAS)

AF:

0.000369

AC:

AN:

84098

European-Finnish (FIN)

AF:

0.00769

AC:

293

AN:

38108

Middle Eastern (MID)

AF:

0.00155

AC:

AN:

5162

European-Non Finnish (NFE)

AF:

0.00739

AC:

8158

AN:

1104420

Other (OTH)

AF:

0.00496

AC:

295

AN:

59456

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

588

1177

1765

2354

2942

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

306

612

918

1224

1530

<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:

0.00462

AC:

703

AN:

152308

Hom.:

Cov.:

AF XY:

0.00427

AC XY:

318

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

41574

American (AMR)

AF:

0.00503

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00668

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00726

AC:

494

AN:

68018

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

111

148

185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00283

Hom.:

Bravo

AF:

0.00433

ExAC

AF:

0.00405

AC:

455

Asia WGS

AF:

0.000578

AC:

AN:

3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 12, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC6A5: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hyperekplexia 3

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hyperekplexia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.025

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0069

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

PhyloP100

0.64

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.19

REVEL

Benign

0.063

Sift

Benign

0.24

Sift4G

Benign

0.35

Polyphen

0.026

Vest4

0.30

MVP

0.71

MPC

0.21

ClinPred

0.010

GERP RS

3.0

Varity_R

0.036

gMVP

0.16

Mutation Taster

=93/7

polymorphism

(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