chr11-20601496-T-C

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.371T>C(p.Phe124Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.767 in 1,613,190 control chromosomes in the GnomAD database, including 475,594 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.79 ( 48038 hom., cov: 34)

Exomes 𝑓: 0.76 ( 427556 hom. )

Consequence

SLC6A5
NM_004211.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.06

Publications

31 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=7.56026E-7).

BP6

Variant 11-20601496-T-C is Benign according to our data. Variant chr11-20601496-T-C is described in ClinVar as Benign. ClinVar VariationId is 304008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

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.371T>C	p.Phe124Ser	missense	Exon 2 of 16	NP_004202.4	Q9Y345-1
	SLC6A5	NM_001318369.2		c.-193T>C		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.371T>C	p.Phe124Ser	missense	Exon 2 of 16	ENSP00000434364.2	Q9Y345-1
	SLC6A5	ENST00000298923.11	TSL:1	n.371T>C		non_coding_transcript_exon	Exon 2 of 15	ENSP00000298923.7	J3KNC4

Frequencies

GnomAD3 genomes

AF:

0.792

AC:

120486

AN:

152072

Hom.:

47993

Cov.:

show subpopulations

Gnomad AFR

AF:

0.877

Gnomad AMI

AF:

0.934

Gnomad AMR

AF:

0.758

Gnomad ASJ

AF:

0.803

Gnomad EAS

AF:

0.761

Gnomad SAS

AF:

0.789

Gnomad FIN

AF:

0.742

Gnomad MID

AF:

0.741

Gnomad NFE

AF:

0.758

Gnomad OTH

AF:

0.765

GnomAD2 exomes

AF:

0.771

AC:

191211

AN:

247878

AF XY:

0.771

show subpopulations

Gnomad AFR exome

AF:

0.877

Gnomad AMR exome

AF:

0.750

Gnomad ASJ exome

AF:

0.817

Gnomad EAS exome

AF:

0.759

Gnomad FIN exome

AF:

0.743

Gnomad NFE exome

AF:

0.762

Gnomad OTH exome

AF:

0.761

GnomAD4 exome

AF:

0.764

AC:

1116844

AN:

1461000

Hom.:

427556

Cov.:

AF XY:

0.765

AC XY:

555791

AN XY:

726766

show subpopulations

African (AFR)

AF:

0.878

AC:

29396

AN:

33468

American (AMR)

AF:

0.750

AC:

33408

AN:

44552

Ashkenazi Jewish (ASJ)

AF:

0.816

AC:

21324

AN:

26118

East Asian (EAS)

AF:

0.792

AC:

31403

AN:

39670

South Asian (SAS)

AF:

0.790

AC:

68070

AN:

86182

European-Finnish (FIN)

AF:

0.745

AC:

39709

AN:

53328

Middle Eastern (MID)

AF:

0.777

AC:

4483

AN:

5766

European-Non Finnish (NFE)

AF:

0.758

AC:

842964

AN:

1111582

Other (OTH)

AF:

0.764

AC:

46087

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

17204

34408

51612

68816

86020

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20408

40816

61224

81632

102040

<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:

0.792

AC:

120586

AN:

152190

Hom.:

48038

Cov.:

AF XY:

0.790

AC XY:

58769

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.877

AC:

36428

AN:

41550

American (AMR)

AF:

0.757

AC:

11588

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.803

AC:

2787

AN:

3472

East Asian (EAS)

AF:

0.761

AC:

3928

AN:

5160

South Asian (SAS)

AF:

0.790

AC:

3812

AN:

4826

European-Finnish (FIN)

AF:

0.742

AC:

7853

AN:

10590

Middle Eastern (MID)

AF:

0.738

AC:

217

AN:

294

European-Non Finnish (NFE)

AF:

0.758

AC:

51502

AN:

67974

Other (OTH)

AF:

0.766

AC:

1619

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1331

2663

3994

5326

6657

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

870

1740

2610

3480

4350

<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:

0.773

Hom.:

167672

Bravo

AF:

0.798

TwinsUK

AF:

0.755

AC:

2801

ALSPAC

AF:

0.754

AC:

2905

ESP6500AA

AF:

0.874

AC:

3850

ESP6500EA

AF:

0.755

AC:

6490

ExAC

AF:

0.773

AC:

93712

Asia WGS

AF:

0.781

AC:

2718

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyperekplexia 3 (3)

Hyperekplexia (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.013

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.076

MetaRNN

Benign

7.6e-7

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

PhyloP100

3.1

PrimateAI

Benign

0.48

PROVEAN

Benign

0.72

REVEL

Benign

0.14

Sift

Benign

0.44

Sift4G

Benign

0.41

Polyphen

0.0

Vest4

0.025

MPC

0.34

ClinPred

0.0031

GERP RS

2.8

Varity_R

0.050

gMVP

0.50

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over