rs17279437

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBA1

The NM_020208.4(SLC6A20):c.596C>T(p.Thr199Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0894 in 1,612,876 control chromosomes in the GnomAD database, including 7,209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.066 ( 424 hom., cov: 32)

Exomes 𝑓: 0.092 ( 6785 hom. )

Consequence

SLC6A20
NM_020208.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 8.14

Publications

72 publications found

Variant links:

Genes affected

SLC6A20 (HGNC:30927): (solute carrier family 6 member 20) Transport of small hydrophilic substances across cell membranes is mediated by substrate-specific transporter proteins which have been classified into several families of related genes. The protein encoded by this gene belongs to the sodium:neurotransmitter symporter (SNF) family and functions as a proline transporter expressed in kidney and small intestine. Mutations in this gene are associated with Hyperglycinuria and Iminoglycinuria. [provided by RefSeq, Jul 2020]

SLC6A20 Gene-Disease associations (from GenCC):

hyperglycinuria
Inheritance: AR, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

SLC6A20 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when AlphaMissense, BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.006226331).

BP6

Variant 3-45772602-G-A is Benign according to our data. Variant chr3-45772602-G-A is described in ClinVar as Benign. ClinVar VariationId is 4845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A20	NM_020208.4 link	c.596C>T	p.Thr199Met	missense_variant	Exon 5 of 11	ENST00000358525.9	NP_064593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC6A20	ENST00000358525.9 link	c.596C>T	p.Thr199Met	missense_variant	Exon 5 of 11	1	NM_020208.4	ENSP00000346298.4
SLC6A20	ENST00000353278.8 link	c.583-1144C>T		intron_variant	Intron 4 of 9	1		ENSP00000296133.5
SLC6A20	ENST00000703343.1 link	c.596C>T	p.Thr199Met	missense_variant	Exon 5 of 11			ENSP00000515266.1
SLC6A20	ENST00000413781.1 link	n.571C>T		non_coding_transcript_exon_variant	Exon 4 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.0659

AC:

10025

AN:

152124

Hom.:

424

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0189

Gnomad AMI

AF:

0.0614

Gnomad AMR

AF:

0.0497

Gnomad ASJ

AF:

0.115

Gnomad EAS

AF:

0.00654

Gnomad SAS

AF:

0.0394

Gnomad FIN

AF:

0.100

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0976

Gnomad OTH

AF:

0.0492

GnomAD2 exomes

AF:

0.0717

AC:

17750

AN:

247566

AF XY:

0.0726

show subpopulations

Gnomad AFR exome

AF:

0.0173

Gnomad AMR exome

AF:

0.0466

Gnomad ASJ exome

AF:

0.116

Gnomad EAS exome

AF:

0.00491

Gnomad FIN exome

AF:

0.104

Gnomad NFE exome

AF:

0.0967

Gnomad OTH exome

AF:

0.0679

GnomAD4 exome

AF:

0.0918

AC:

134120

AN:

1460634

Hom.:

6785

Cov.:

AF XY:

0.0903

AC XY:

65619

AN XY:

726600

show subpopulations

African (AFR)

AF:

0.0132

AC:

441

AN:

33466

American (AMR)

AF:

0.0471

AC:

2102

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.115

AC:

3003

AN:

26112

East Asian (EAS)

AF:

0.00912

AC:

362

AN:

39674

South Asian (SAS)

AF:

0.0404

AC:

3482

AN:

86090

European-Finnish (FIN)

AF:

0.0997

AC:

5306

AN:

53202

Middle Eastern (MID)

AF:

0.0244

AC:

141

AN:

5768

European-Non Finnish (NFE)

AF:

0.103

AC:

114459

AN:

1111334

Other (OTH)

AF:

0.0799

AC:

4824

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

6136

12272

18409

24545

30681

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4140

8280

12420

16560

20700

<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:

0.0659

AC:

10030

AN:

152242

Hom.:

424

Cov.:

AF XY:

0.0648

AC XY:

4826

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0188

AC:

781

AN:

41544

American (AMR)

AF:

0.0499

AC:

764

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.115

AC:

398

AN:

3466

East Asian (EAS)

AF:

0.00656

AC:

AN:

5186

South Asian (SAS)

AF:

0.0396

AC:

191

AN:

4820

European-Finnish (FIN)

AF:

0.100

AC:

1064

AN:

10600

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0976

AC:

6635

AN:

68002

Other (OTH)

AF:

0.0487

AC:

103

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

483

966

1449

1932

2415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<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:

0.0847

Hom.:

2555

Bravo

AF:

0.0596

TwinsUK

AF:

0.0909

AC:

337

ALSPAC

AF:

0.102

AC:

392

ESP6500AA

AF:

0.0204

AC:

ESP6500EA

AF:

0.0994

AC:

837

ExAC

AF:

0.0702

AC:

8496

Asia WGS

AF:

0.0270

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperglycinuria

Benign:2Other:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2008

OMIM

Significance:Affects

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19033659, 21572414) -

SLC6A20-related disorder

Benign:1

Dec 04, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;T;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D

MetaRNN

Benign

0.0062

T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Pathogenic

4.2

H;.;.

PhyloP100

8.1

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-5.5

D;D;D

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.58

MPC

0.88

ClinPred

0.079

GERP RS

5.3

Varity_R

0.84

gMVP

0.83

Mutation Taster

=87/13

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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