rs2276432

chr11-20654707-T-C

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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. 2/2 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002398
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.912

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 304038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-20654707-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
SLC6A5	NM_004211.5	c.2239-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000525748.6
SLC6A5	NM_001318369.2	c.1537-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
SLC6A5	XM_017018544.3	c.1363-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
SLC6A5	XR_007062528.1	n.1617-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A5	ENST00000525748.6	c.2239-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004211.5	P1
SLC6A5	ENST00000298923.11	c.*1536-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1
SLC6A5	ENST00000528440.1	n.770-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.153 AC: 38579 AN: 251424 Hom.: 3246 AF XY: 0.157 AC XY: 21392 AN XY: 135904

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 SAS exome AF: 0.179

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

Gnomad4 AFR exome AF: 0.206

Gnomad4 AMR exome AF: 0.0839

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.0622

Gnomad4 SAS exome AF: 0.180

Gnomad4 FIN exome AF: 0.214

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.158

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

Gnomad4 AFR AF: 0.201

Gnomad4 AMR AF: 0.120

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.0555

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.218

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.172

Alfa AF: 0.168 Hom.: 3551

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperekplexia 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	11
Dann	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs2276432; hg19: chr11-20676253;