11-20622581-A-T

Variant names:

• chr11-20622581-A-T
• rs883377
• NM_004211.5:c.1261-4127A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004211.5(SLC6A5):​c.1261-4127A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.718 in 152,068 control chromosomes in the GnomAD database, including 39,405 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.72 (39405 hom., cov: 32)
• Consequence: SLC6A5 NM_004211.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00
• Publications: 3 publications found

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 Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.851 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A5	NM_004211.5	MANE Select	c.1261-4127A>T		intron	N/A	NP_004202.4
	SLC6A5	NM_001318369.2		c.559-4127A>T		intron	N/A	NP_001305298.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A5	ENST00000525748.6	TSL:1 MANE Select	c.1261-4127A>T		intron	N/A	ENSP00000434364.2
	SLC6A5	ENST00000298923.11	TSL:1	n.*558-4127A>T		intron	N/A	ENSP00000298923.7

Frequencies

GnomAD3 genomes AF: 0.718 AC: 109107 AN: 151950 Hom.: 39374 Cov.: 32

Gnomad AFR AF: 0.696

Gnomad AMI AF: 0.713

Gnomad AMR AF: 0.783

Gnomad ASJ AF: 0.731

Gnomad EAS AF: 0.872

Gnomad SAS AF: 0.807

Gnomad FIN AF: 0.695

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.702

Gnomad OTH AF: 0.717

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.718 AC: 109182 AN: 152068 Hom.: 39405 Cov.: 32 AF XY: 0.722 AC XY: 53643 AN XY: 74334

African (AFR) AF: 0.696 AC: 28876 AN: 41492

American (AMR) AF: 0.784 AC: 11985 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.731 AC: 2537 AN: 3472

East Asian (EAS) AF: 0.873 AC: 4499 AN: 5156

South Asian (SAS) AF: 0.807 AC: 3891 AN: 4820

European-Finnish (FIN) AF: 0.695 AC: 7354 AN: 10576

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.702 AC: 47680 AN: 67946

Other (OTH) AF: 0.717 AC: 1511 AN: 2108

Alfa AF: 0.710 Hom.: 4767

Bravo AF: 0.726

Asia WGS AF: 0.830 AC: 2886 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.87
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs883377; hg19: chr11-20644127;