rs2276432

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, 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 -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.

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.2239-6T>C		splice_region intron	N/A	NP_004202.4	Q9Y345-1
	SLC6A5	NM_001318369.2		c.1537-6T>C		splice_region 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.2239-6T>C		splice_region intron	N/A	ENSP00000434364.2	Q9Y345-1
	SLC6A5	ENST00000298923.11	TSL:1	n.*1536-6T>C		splice_region intron	N/A	ENSP00000298923.7	J3KNC4
	SLC6A5	ENST00000528440.1	TSL:5	n.770-6T>C		splice_region intron	N/A

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hyperekplexia 3 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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;