chr11-20601391-C-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004211.5(SLC6A5):c.266C>A(p.Ala89Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0278 in 1,603,806 control chromosomes in the GnomAD database, including 739 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 43 hom., cov: 33)

Exomes 𝑓: 0.028 ( 696 hom. )

Consequence

SLC6A5
NM_004211.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.905

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025437474).

BP6

Variant 11-20601391-C-A is Benign according to our data. Variant chr11-20601391-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 304001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-20601391-C-A is described in Lovd as [Benign]. Variant chr11-20601391-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0215 (3280/152332) while in subpopulation NFE AF= 0.0332 (2259/68012). AF 95% confidence interval is 0.0321. There are 43 homozygotes in gnomad4. There are 1553 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A5	NM_004211.5 link	c.266C>A	p.Ala89Glu	missense_variant	Exon 2 of 16	ENST00000525748.6	NP_004202.4	Q9Y345-1Q4VAM4Q4VAM6
SLC6A5	NM_001318369.2 link	c.-298C>A		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.266C>A	p.Ala89Glu	missense_variant	Exon 2 of 16	1	NM_004211.5	ENSP00000434364.2		Q9Y345-1
SLC6A5	ENST00000298923.11 link	n.266C>A		non_coding_transcript_exon_variant	Exon 2 of 15	1		ENSP00000298923.7		J3KNC4

Frequencies

GnomAD3 genomes

AF:

0.0216

AC:

3282

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00612

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0199

Gnomad ASJ

AF:

0.0230

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.0261

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0332

Gnomad OTH

AF:

0.0292

GnomAD3 exomes

AF:

0.0208

AC:

4627

AN:

221962

Hom.:

AF XY:

0.0212

AC XY:

2587

AN XY:

121928

show subpopulations

Gnomad AFR exome

AF:

0.00452

Gnomad AMR exome

AF:

0.0134

Gnomad ASJ exome

AF:

0.0259

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00629

Gnomad FIN exome

AF:

0.0261

Gnomad NFE exome

AF:

0.0316

Gnomad OTH exome

AF:

0.0247

GnomAD4 exome

AF:

0.0285

AC:

41297

AN:

1451474

Hom.:

696

Cov.:

AF XY:

0.0280

AC XY:

20192

AN XY:

721464

show subpopulations

Gnomad4 AFR exome

AF:

0.00513

Gnomad4 AMR exome

AF:

0.0140

Gnomad4 ASJ exome

AF:

0.0262

Gnomad4 EAS exome

AF:

0.0000510

Gnomad4 SAS exome

AF:

0.00673

Gnomad4 FIN exome

AF:

0.0276

Gnomad4 NFE exome

AF:

0.0327

Gnomad4 OTH exome

AF:

0.0248

GnomAD4 genome

AF:

0.0215

AC:

3280

AN:

152332

Hom.:

Cov.:

AF XY:

0.0208

AC XY:

1553

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00613

Gnomad4 AMR

AF:

0.0198

Gnomad4 ASJ

AF:

0.0230

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.00559

Gnomad4 FIN

AF:

0.0261

Gnomad4 NFE

AF:

0.0332

Gnomad4 OTH

AF:

0.0289

Alfa

AF:

0.0302

Hom.:

Bravo

AF:

0.0202

TwinsUK

AF:

0.0383

AC:

142

ALSPAC

AF:

0.0335

AC:

129

ESP6500AA

AF:

0.00665

AC:

ESP6500EA

AF:

0.0322

AC:

274

ExAC

AF:

0.0197

AC:

2369

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperekplexia 3

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 303/12870=2.3% -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hyperekplexia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.033

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.1

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.26

REVEL

Benign

0.13

Sift

Uncertain

0.024

Sift4G

Benign

0.13

Polyphen

0.089

Vest4

0.13

MPC

0.26

ClinPred

0.0065

GERP RS

1.9

Varity_R

0.21

gMVP

0.49

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

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