rs2000959

Variant names:

• chr11-20637133-C-A
• rs2000959
• NM_004211.5:c.1738-39C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-20637133-C-A
• chr11-20637133-C-G

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.1738-39C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 1,606,736 control chromosomes in the GnomAD database, including 89,865 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7409 hom., cov: 30)
  • Exomes 𝑓: 0.33 (82456 hom.)
• Consequence: SLC6A5 NM_004211.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.07
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-20637133-C-A is Benign according to our data. Variant chr11-20637133-C-A is described in ClinVar as Benign. ClinVar VariationId is 1294497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A5	NM_004211.5	c.1738-39C>A		intron_variant	Intron 11 of 15	ENST00000525748.6	NP_004202.4
SLC6A5	NM_001318369.2	c.1036-39C>A		intron_variant	Intron 10 of 14		NP_001305298.1
SLC6A5	XM_017018544.3	c.862-39C>A		intron_variant	Intron 7 of 11		XP_016874033.1
SLC6A5	XR_007062528.1	n.1116-39C>A		intron_variant	Intron 8 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A5	ENST00000525748.6	c.1738-39C>A		intron_variant	Intron 11 of 15	1	NM_004211.5	ENSP00000434364.2
SLC6A5	ENST00000298923.11	n.*1035-39C>A		intron_variant	Intron 10 of 14	1		ENSP00000298923.7
SLC6A5	ENST00000528440.1	n.269-39C>A		intron_variant	Intron 3 of 7	5

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45277 AN: 151666 Hom.: 7389 Cov.: 30

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.311

GnomAD2 exomes AF: 0.366 AC: 91911 AN: 251264 AF XY: 0.369

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.550

Gnomad ASJ exome AF: 0.380

Gnomad EAS exome AF: 0.354

Gnomad FIN exome AF: 0.329

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.329 AC: 478604 AN: 1454954 Hom.: 82456 Cov.: 31 AF XY: 0.334 AC XY: 242161 AN XY: 724206

African (AFR) AF: 0.168 AC: 5595 AN: 33358

American (AMR) AF: 0.534 AC: 23880 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 9950 AN: 26068

East Asian (EAS) AF: 0.381 AC: 15088 AN: 39650

South Asian (SAS) AF: 0.493 AC: 42396 AN: 86076

European-Finnish (FIN) AF: 0.328 AC: 17481 AN: 53326

Middle Eastern (MID) AF: 0.303 AC: 1739 AN: 5746

European-Non Finnish (NFE) AF: 0.310 AC: 342692 AN: 1105896

Other (OTH) AF: 0.329 AC: 19783 AN: 60148

GnomAD4 genome AF: 0.299 AC: 45310 AN: 151782 Hom.: 7409 Cov.: 30 AF XY: 0.307 AC XY: 22739 AN XY: 74178

African (AFR) AF: 0.176 AC: 7294 AN: 41432

American (AMR) AF: 0.423 AC: 6446 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 1317 AN: 3468

East Asian (EAS) AF: 0.359 AC: 1842 AN: 5138

South Asian (SAS) AF: 0.497 AC: 2364 AN: 4760

European-Finnish (FIN) AF: 0.332 AC: 3496 AN: 10534

Middle Eastern (MID) AF: 0.301 AC: 88 AN: 292

European-Non Finnish (NFE) AF: 0.317 AC: 21505 AN: 67896

Other (OTH) AF: 0.316 AC: 665 AN: 2104

Alfa AF: 0.315 Hom.: 33508

Bravo AF: 0.297

Asia WGS AF: 0.440 AC: 1529 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 22, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hyperekplexia 3 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.033
DANN	Benign	0.49
PhyloP100		-4.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2000959; hg19: chr11-20658679; COSMIC: COSV54227428;