11-20601520-C-G

Position:

chr11-20601520-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_004211.5(SLC6A5):c.395C>G(p.Ala132Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00329 in 1,614,088 control chromosomes in the GnomAD database, including 188 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 91 hom., cov: 34)

Exomes 𝑓: 0.0018 ( 97 hom. )

Consequence

SLC6A5
NM_004211.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.00

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 11-20601520-C-G is Benign according to our data. Variant chr11-20601520-C-G is described in ClinVar as [Benign]. Clinvar id is 304009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-20601520-C-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A5	NM_004211.5 link	c.395C>G	p.Ala132Gly	missense_variant	2/16	ENST00000525748.6	NP_004202.4	Q9Y345-1Q4VAM4Q4VAM6
SLC6A5	NM_001318369.2 link	c.-169C>G		5_prime_UTR_variant	2/15		NP_001305298.1	Q9Y345-2Q4VAM4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A5	ENST00000525748.6 link	c.395C>G	p.Ala132Gly	missense_variant	2/16	1	NM_004211.5	ENSP00000434364.2		Q9Y345-1
SLC6A5	ENST00000298923.11 link	n.395C>G		non_coding_transcript_exon_variant	2/15	1		ENSP00000298923.7		J3KNC4

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2630

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00595

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.00467

AC:

1166

AN:

249908

Hom.:

AF XY:

0.00359

AC XY:

486

AN XY:

135398

show subpopulations

Gnomad AFR exome

AF:

0.0644

Gnomad AMR exome

AF:

0.00264

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000177

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.00183

AC:

2671

AN:

1461772

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

1162

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0655

Gnomad4 AMR exome

AF:

0.00288

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000728

Gnomad4 OTH exome

AF:

0.00384

GnomAD4 genome

AF:

0.0173

AC:

2637

AN:

152316

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

1250

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0603

Gnomad4 AMR

AF:

0.00595

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.00137

Hom.:

Bravo

AF:

0.0199

ESP6500AA

AF:

0.0629

AC:

277

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00577

AC:

701

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperekplexia 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Hyperekplexia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

SLC6A5-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2024

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

0.068

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.032

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.0

REVEL

Benign

0.066

Sift

Benign

0.19

Sift4G

Uncertain

0.0030

Polyphen

0.18

Vest4

0.10

MVP

0.37

MPC

0.20

ClinPred

0.0017

GERP RS

-3.5

Varity_R

0.055

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.28

Position offset: -37

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over