chr11-20600983-C-A

Variant names:

• chr11-20600983-C-A
• rs76017471
• NM_004211.5:c.4-146C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004211.5(SLC6A5):​c.4-146C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 758,616 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (64 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (21 hom.)
• Consequence: SLC6A5 NM_004211.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.65
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-20600983-C-A is Benign according to our data. Variant chr11-20600983-C-A is described in ClinVar as Benign. ClinVar VariationId is 1269491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0503 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A5	NM_004211.5	MANE Select	c.4-146C>A		intron	N/A	NP_004202.4	Q9Y345-1
	SLC6A5	NM_001318369.2		c.-560-146C>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.4-146C>A		intron	N/A	ENSP00000434364.2	Q9Y345-1
	SLC6A5	ENST00000298923.11	TSL:1	n.4-146C>A		intron	N/A	ENSP00000298923.7	J3KNC4

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2240 AN: 152162 Hom.: 63 Cov.: 33

Gnomad AFR AF: 0.0521

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.00133 AC: 805 AN: 606336 Hom.: 21 AF XY: 0.00110 AC XY: 343 AN XY: 312686

African (AFR) AF: 0.0490 AC: 657 AN: 13398

American (AMR) AF: 0.00217 AC: 35 AN: 16128

Ashkenazi Jewish (ASJ) AF: 0.000139 AC: 2 AN: 14366

East Asian (EAS) AF: 0.00 AC: 0 AN: 29852

South Asian (SAS) AF: 0.0000642 AC: 3 AN: 46696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29762

Middle Eastern (MID) AF: 0.000788 AC: 2 AN: 2538

European-Non Finnish (NFE) AF: 0.0000284 AC: 12 AN: 422710

Other (OTH) AF: 0.00304 AC: 94 AN: 30886

GnomAD4 genome AF: 0.0148 AC: 2249 AN: 152280 Hom.: 64 Cov.: 33 AF XY: 0.0142 AC XY: 1056 AN XY: 74462

African (AFR) AF: 0.0522 AC: 2167 AN: 41540

American (AMR) AF: 0.00366 AC: 56 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68030

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.0126 Hom.: 6

Bravo AF: 0.0167

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.0
DANN	Benign	0.52
PhyloP100		-1.6
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: rs76017471; hg19: chr11-20622529;