rs121908493

Positions:

chr11-20617755-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_004211.5(SLC6A5):c.1131C>A(p.Tyr377Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

SLC6A5
NM_004211.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.11

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-20617755-C-A is Pathogenic according to our data. Variant chr11-20617755-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 5761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SLC6A5	NM_004211.5 linkuse as main transcript	c.1131C>A	p.Tyr377Ter	stop_gained	7/16	ENST00000525748.6	NP_004202.4
SLC6A5	NM_001318369.2 linkuse as main transcript	c.429C>A	p.Tyr143Ter	stop_gained	6/15		NP_001305298.1
SLC6A5	XM_017018544.3 linkuse as main transcript	c.255C>A	p.Tyr85Ter	stop_gained	3/12		XP_016874033.1
SLC6A5	XR_007062528.1 linkuse as main transcript	n.509C>A		non_coding_transcript_exon_variant	4/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A5	ENST00000525748.6 linkuse as main transcript	c.1131C>A	p.Tyr377Ter	stop_gained	7/16	1	NM_004211.5	ENSP00000434364	P1	Q9Y345-1
SLC6A5	ENST00000298923.11 linkuse as main transcript	c.*428C>A		3_prime_UTR_variant, NMD_transcript_variant	6/15	1		ENSP00000298923

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251474

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461542

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000324

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000322

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperekplexia 3

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 30, 2023	This variant is present in population databases (rs121908493, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Tyr377*) in the SLC6A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC6A5 are known to be pathogenic (PMID: 14622583, 16751771, 22700964). This premature translational stop signal has been observed in individuals with hyperekplexia (PMID: 16751771, 16884688). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 5761). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.1131C>A;p.(Tyr377) variant creates a premature translational stop signal in the SLC6A5 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 5761; PMID: 16884688; 16751771; 31604777; 32714574; 22114948; 29859229; 18707791; 22700964; 33310157) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 16884688) - PS3_supporting. The variant is present at low allele frequencies population databases (rs121908493 – gnomAD 0.003285%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Tyr377) was detected in trans with a pathogenic variant (PMID: 16751771) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 16884688) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Oct 04, 2012	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.61

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.055

FATHMM_MKL

Uncertain

0.82

MutationTaster

Benign

1.0

Vest4

0.94

GERP RS

-0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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