rs2241941

Variant names:

• chr11-20601477-C-T
• rs2241941
• NM_004211.5:c.352C>T
• SLC6A5 p.Leu118Leu

Your query was ambiguous. Multiple possible variants found:

• chr11-20601477-C-T
• chr11-20601477-C-A
• chr11-20601477-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_001318369.2(SLC6A5):​c.-212C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 1,611,814 control chromosomes in the GnomAD database, including 90,109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8118 hom., cov: 34)
  • Exomes 𝑓: 0.33 (81991 hom.)
• Consequence: SLC6A5 NM_001318369.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.752
• Publications: 19 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: AD, AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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=-0.62).
• BP6: Variant 11-20601477-C-T is Benign according to our data. Variant chr11-20601477-C-T is described in ClinVar as Benign. ClinVar VariationId is 304006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318369.2. 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.352C>T	p.Leu118Leu	synonymous	Exon 2 of 16	NP_004202.4	Q9Y345-1
	SLC6A5	NM_001318369.2		c.-212C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 15	NP_001305298.1	Q9Y345-2
	SLC6A5	NM_001318369.2		c.-212C>T		5_prime_UTR	Exon 2 of 15	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.352C>T	p.Leu118Leu	synonymous	Exon 2 of 16	ENSP00000434364.2	Q9Y345-1
	SLC6A5	ENST00000298923.11	TSL:1	n.352C>T		non_coding_transcript_exon	Exon 2 of 15	ENSP00000298923.7	J3KNC4

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49306 AN: 152020 Hom.: 8101 Cov.: 34

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.324

GnomAD2 exomes AF: 0.331 AC: 80808 AN: 243960 AF XY: 0.328

Gnomad AFR exome AF: 0.309

Gnomad AMR exome AF: 0.337

Gnomad ASJ exome AF: 0.328

Gnomad EAS exome AF: 0.354

Gnomad FIN exome AF: 0.378

Gnomad NFE exome AF: 0.337

Gnomad OTH exome AF: 0.319

GnomAD4 exome AF: 0.334 AC: 487354 AN: 1459676 Hom.: 81991 Cov.: 71 AF XY: 0.331 AC XY: 240399 AN XY: 726028

African (AFR) AF: 0.301 AC: 10054 AN: 33448

American (AMR) AF: 0.335 AC: 14857 AN: 44348

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 8568 AN: 26078

East Asian (EAS) AF: 0.394 AC: 15598 AN: 39624

South Asian (SAS) AF: 0.274 AC: 23529 AN: 85996

European-Finnish (FIN) AF: 0.380 AC: 20194 AN: 53164

Middle Eastern (MID) AF: 0.287 AC: 1652 AN: 5764

European-Non Finnish (NFE) AF: 0.336 AC: 373824 AN: 1111004

Other (OTH) AF: 0.317 AC: 19078 AN: 60250

GnomAD4 genome AF: 0.324 AC: 49358 AN: 152138 Hom.: 8118 Cov.: 34 AF XY: 0.325 AC XY: 24153 AN XY: 74380

African (AFR) AF: 0.308 AC: 12776 AN: 41516

American (AMR) AF: 0.313 AC: 4792 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1152 AN: 3472

East Asian (EAS) AF: 0.358 AC: 1845 AN: 5150

South Asian (SAS) AF: 0.276 AC: 1334 AN: 4828

European-Finnish (FIN) AF: 0.373 AC: 3943 AN: 10584

Middle Eastern (MID) AF: 0.272 AC: 79 AN: 290

European-Non Finnish (NFE) AF: 0.330 AC: 22439 AN: 67982

Other (OTH) AF: 0.320 AC: 676 AN: 2114

Alfa AF: 0.326 Hom.: 23454

Bravo AF: 0.326

Asia WGS AF: 0.286 AC: 994 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Hyperekplexia 3 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	9.2
DANN	Benign	0.89
PhyloP100		0.75
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2241941;

hg19: chr11-20623023;

COSMIC: COSV54223263;