chr11-20654707-T-C

Variant names:

• chr11-20654707-T-C
• rs2276432
• NM_004211.5:c.2239-6T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004211.5(SLC6A5):​c.2239-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,613,592 control chromosomes in the GnomAD database, including 23,544 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2403 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21141 hom.)
• Consequence: SLC6A5 NM_004211.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002398
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.912
• Publications: 10 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 11-20654707-T-C is Benign according to our data. Variant chr11-20654707-T-C is described in ClinVar as Benign. ClinVar VariationId is 304038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A5	NM_004211.5	c.2239-6T>C		splice_region_variant, intron_variant	Intron 15 of 15	ENST00000525748.6	NP_004202.4
SLC6A5	NM_001318369.2	c.1537-6T>C		splice_region_variant, intron_variant	Intron 14 of 14		NP_001305298.1
SLC6A5	XM_017018544.3	c.1363-6T>C		splice_region_variant, intron_variant	Intron 11 of 11		XP_016874033.1
SLC6A5	XR_007062528.1	n.1617-6T>C		splice_region_variant, intron_variant	Intron 12 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A5	ENST00000525748.6	c.2239-6T>C		splice_region_variant, intron_variant	Intron 15 of 15	1	NM_004211.5	ENSP00000434364.2
SLC6A5	ENST00000298923.11	n.*1536-6T>C		splice_region_variant, intron_variant	Intron 14 of 14	1		ENSP00000298923.7
SLC6A5	ENST00000528440.1	n.770-6T>C		splice_region_variant, intron_variant	Intron 7 of 7	5

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26224 AN: 152004 Hom.: 2400 Cov.: 32

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.0556

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.171

GnomAD2 exomes AF: 0.153 AC: 38579 AN: 251424 AF XY: 0.157

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0811

Gnomad ASJ exome AF: 0.110

Gnomad EAS exome AF: 0.0496

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.171

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.167 AC: 243521 AN: 1461470 Hom.: 21141 Cov.: 33 AF XY: 0.168 AC XY: 121895 AN XY: 727078

African (AFR) AF: 0.206 AC: 6901 AN: 33472

American (AMR) AF: 0.0839 AC: 3754 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2912 AN: 26130

East Asian (EAS) AF: 0.0622 AC: 2468 AN: 39698

South Asian (SAS) AF: 0.180 AC: 15505 AN: 86242

European-Finnish (FIN) AF: 0.214 AC: 11428 AN: 53410

Middle Eastern (MID) AF: 0.172 AC: 990 AN: 5760

European-Non Finnish (NFE) AF: 0.171 AC: 190018 AN: 1111656

Other (OTH) AF: 0.158 AC: 9545 AN: 60378

GnomAD4 genome AF: 0.173 AC: 26245 AN: 152122 Hom.: 2403 Cov.: 32 AF XY: 0.174 AC XY: 12926 AN XY: 74358

African (AFR) AF: 0.201 AC: 8346 AN: 41494

American (AMR) AF: 0.120 AC: 1831 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 403 AN: 3462

East Asian (EAS) AF: 0.0555 AC: 287 AN: 5168

South Asian (SAS) AF: 0.176 AC: 847 AN: 4814

European-Finnish (FIN) AF: 0.218 AC: 2310 AN: 10584

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11726 AN: 67996

Other (OTH) AF: 0.172 AC: 362 AN: 2108

Alfa AF: 0.168 Hom.: 4308

Bravo AF: 0.163

Asia WGS AF: 0.134 AC: 465 AN: 3478

EpiCase AF: 0.165

EpiControl AF: 0.169

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperekplexia 3 Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

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	-0.46
CADD	Benign	11
DANN	Benign	0.80
PhyloP100		0.91
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2276432; hg19: chr11-20676253;