dbSNP rs2248632: SLC6A9:c.1435+22C>T (chr1-44000934-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_001024845.3(SLC6A9):c.1435+22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0883 in 1,601,346 control chromosomes in the GnomAD database, including 8,154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1746 hom., cov: 33)

Exomes 𝑓: 0.084 ( 6408 hom. )

Consequence

SLC6A9
NM_001024845.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.10

Publications

15 publications found

Variant links:

Genes affected

SLC6A9 (HGNC:11056): (solute carrier family 6 member 9) The amino acid glycine acts as an inhibitory neurotransmitter in the central nervous system. The protein encoded by this gene is one of two transporters that stop glycine signaling by removing it from the synaptic cleft. [provided by RefSeq, Jun 2016]

SLC6A9 Gene-Disease associations (from GenCC):

atypical glycine encephalopathy
Inheritance: AR, Unknown Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
infantile glycine encephalopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC6A9 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=0.016821086).

BP6

Variant 1-44000934-G-A is Benign according to our data. Variant chr1-44000934-G-A is described in ClinVar as Benign. ClinVar VariationId is 1179904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A9	NM_001024845.3 link	c.1435+22C>T		intron_variant	Intron 11 of 13	ENST00000372310.8	NP_001020016.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A9	ENST00000372310.8 link	c.1435+22C>T		intron_variant	Intron 11 of 13	5	NM_001024845.3	ENSP00000361384.4		P48067-2

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19666

AN:

152118

Hom.:

1739

Cov.:

show subpopulations

Gnomad AFR

AF:

0.241

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.122

Gnomad ASJ

AF:

0.0720

Gnomad EAS

AF:

0.161

Gnomad SAS

AF:

0.106

Gnomad FIN

AF:

0.125

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.0669

Gnomad OTH

AF:

0.124

GnomAD2 exomes

AF:

0.108

AC:

26380

AN:

243626

AF XY:

0.104

show subpopulations

Gnomad AFR exome

AF:

0.244

Gnomad AMR exome

AF:

0.148

Gnomad ASJ exome

AF:

0.0691

Gnomad EAS exome

AF:

0.152

Gnomad FIN exome

AF:

0.116

Gnomad NFE exome

AF:

0.0703

Gnomad OTH exome

AF:

0.102

GnomAD4 exome

AF:

0.0840

AC:

121657

AN:

1449108

Hom.:

6408

Cov.:

AF XY:

0.0837

AC XY:

60256

AN XY:

719804

show subpopulations

African (AFR)

AF:

0.248

AC:

8217

AN:

33158

American (AMR)

AF:

0.147

AC:

6415

AN:

43668

Ashkenazi Jewish (ASJ)

AF:

0.0710

AC:

1809

AN:

25480

East Asian (EAS)

AF:

0.199

AC:

7840

AN:

39488

South Asian (SAS)

AF:

0.114

AC:

9672

AN:

84640

European-Finnish (FIN)

AF:

0.114

AC:

6048

AN:

53090

Middle Eastern (MID)

AF:

0.137

AC:

781

AN:

5706

European-Non Finnish (NFE)

AF:

0.0680

AC:

75128

AN:

1104052

Other (OTH)

AF:

0.0961

AC:

5747

AN:

59826

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

5871

11742

17613

23484

29355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3086

6172

9258

12344

15430

<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:

0.129

AC:

19709

AN:

152238

Hom.:

1746

Cov.:

AF XY:

0.131

AC XY:

9753

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.242

AC:

10032

AN:

41516

American (AMR)

AF:

0.122

AC:

1871

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0720

AC:

250

AN:

3470

East Asian (EAS)

AF:

0.162

AC:

836

AN:

5172

South Asian (SAS)

AF:

0.106

AC:

514

AN:

4830

European-Finnish (FIN)

AF:

0.125

AC:

1322

AN:

10604

Middle Eastern (MID)

AF:

0.190

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0669

AC:

4552

AN:

68016

Other (OTH)

AF:

0.122

AC:

258

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

842

1685

2527

3370

4212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

204

408

612

816

1020

<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:

0.111

Hom.:

413

Bravo

AF:

0.135

TwinsUK

AF:

0.0650

AC:

241

ALSPAC

AF:

0.0682

AC:

263

ESP6500AA

AF:

0.235

AC:

1036

ESP6500EA

AF:

0.0656

AC:

564

ExAC

AF:

0.109

AC:

13278

Asia WGS

AF:

0.133

AC:

461

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 16, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.53

MetaRNN

Benign

0.017

MetaSVM

Benign

-1.1

PhyloP100

1.1

PROVEAN

Benign

0.74

REVEL

Benign

0.11

Sift

Benign

0.031

Sift4G

Uncertain

0.0040

Vest4

0.096

ClinPred

0.0031

GERP RS

3.3

Mutation Taster

=98/2

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