11-20599640-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004211.5(SLC6A5):c.-33C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0978 in 1,613,326 control chromosomes in the GnomAD database, including 8,349 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (645 hom., cov: 32)
  • Exomes 𝑓: 0.099 (7704 hom.)
• Consequence: SLC6A5 NM_004211.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.772

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 11-20599640-C-T is Benign according to our data. Variant chr11-20599640-C-T is described in ClinVar as [Benign]. Clinvar id is 303991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A5	NM_004211.5	c.-33C>T		5_prime_UTR_variant	1/16	ENST00000525748.6
SLC6A5	NM_001318369.2	c.-596C>T		5_prime_UTR_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A5	ENST00000525748.6	c.-33C>T		5_prime_UTR_variant	1/16	1	NM_004211.5	P1
SLC6A5	ENST00000298923.11	c.-33C>T		5_prime_UTR_variant, NMD_transcript_variant	1/15	1

Frequencies

GnomAD3 genomes AF: 0.0860 AC: 13079 AN: 152140 Hom.: 644 Cov.: 32

Gnomad AFR AF: 0.0606

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0603

Gnomad ASJ AF: 0.0954

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0944

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0979

GnomAD3 exomes AF: 0.0870 AC: 21878 AN: 251464 Hom.: 1138 AF XY: 0.0919 AC XY: 12490 AN XY: 135904

Gnomad AFR exome AF: 0.0586

Gnomad AMR exome AF: 0.0418

Gnomad ASJ exome AF: 0.0977

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.104

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.0902

GnomAD4 exome AF: 0.0990 AC: 144648 AN: 1461068 Hom.: 7704 Cov.: 31 AF XY: 0.0996 AC XY: 72382 AN XY: 726884

Gnomad4 AFR exome AF: 0.0621

Gnomad4 AMR exome AF: 0.0430

Gnomad4 ASJ exome AF: 0.0974

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.105

Gnomad4 OTH exome AF: 0.0937

GnomAD4 genome AF: 0.0859 AC: 13076 AN: 152258 Hom.: 645 Cov.: 32 AF XY: 0.0872 AC XY: 6488 AN XY: 74420

Gnomad4 AFR AF: 0.0605

Gnomad4 AMR AF: 0.0602

Gnomad4 ASJ AF: 0.0954

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0941

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.0959

Alfa AF: 0.0953 Hom.: 186

Bravo AF: 0.0797

Asia WGS AF: 0.0470 AC: 163 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2021

- -

Hyperekplexia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	13
Dann	Benign	0.84

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

Other links and lift over

dbSNP: rs76857783; hg19: chr11-20621186;