chr11-20601117-T-A

Variant names:

• chr11-20601117-T-A
• rs1463209277
• NM_004211.5:c.4-12T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004211.5(SLC6A5):​c.4-12T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,431,312 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SLC6A5 NM_004211.5 intron
• Scores: Splicing: ADA: 0.9045
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.00
• Publications: 0 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, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A5	NM_004211.5	MANE Select	c.4-12T>A		intron	N/A	NP_004202.4	Q9Y345-1
	SLC6A5	NM_001318369.2		c.-560-12T>A		intron	N/A	NP_001305298.1	Q9Y345-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A5	ENST00000525748.6	TSL:1 MANE Select	c.4-12T>A		intron	N/A	ENSP00000434364.2	Q9Y345-1
	SLC6A5	ENST00000298923.11	TSL:1	n.4-12T>A		intron	N/A	ENSP00000298923.7	J3KNC4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000497 AC: 1 AN: 201010 AF XY: 0.00000906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000317

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1431312 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 710712

African (AFR) AF: 0.00 AC: 0 AN: 33168

American (AMR) AF: 0.0000236 AC: 1 AN: 42430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25774

East Asian (EAS) AF: 0.00 AC: 0 AN: 39174

South Asian (SAS) AF: 0.00 AC: 0 AN: 83478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104454

Other (OTH) AF: 0.00 AC: 0 AN: 59660

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Benign	0.90
PhyloP100		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Benign	0.63
SpliceAI score (max)		0.050		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: rs1463209277; hg19: chr11-20622663;