11-20599640-C-T

Variant names:

• chr11-20599640-C-T
• rs76857783
• NM_004211.5:c.-33C>T

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.-33C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0978 in 1,613,326 control chromosomes in the GnomAD database, including 8,349 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (645 hom., cov: 32)
  • Exomes 𝑓: 0.099 (7704 hom.)
• Consequence: SLC6A5 NM_004211.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.772
• Publications: 5 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.66).
• BP6: Variant 11-20599640-C-T is Benign according to our data. Variant chr11-20599640-C-T is described in ClinVar as Benign. ClinVar VariationId is 303991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.104 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.-33C>T		5_prime_UTR	Exon 1 of 16	NP_004202.4	Q9Y345-1
	SLC6A5	NM_001318369.2		c.-596C>T		5_prime_UTR	Exon 1 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.-33C>T		5_prime_UTR	Exon 1 of 16	ENSP00000434364.2	Q9Y345-1
	SLC6A5	ENST00000298923.11	TSL:1	n.-33C>T		non_coding_transcript_exon	Exon 1 of 15	ENSP00000298923.7	J3KNC4
	SLC6A5	ENST00000298923.11	TSL:1	n.-33C>T		5_prime_UTR	Exon 1 of 15	ENSP00000298923.7	J3KNC4

Frequencies

GnomAD3 genomes AF: 0.0860 AC: 13079 AN: 152140 Hom.: 644 Cov.: 32

Gnomad AFR AF: 0.0606

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0603

Gnomad ASJ AF: 0.0954

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0944

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0979

GnomAD2 exomes AF: 0.0870 AC: 21878 AN: 251464 AF XY: 0.0919

Gnomad AFR exome AF: 0.0586

Gnomad AMR exome AF: 0.0418

Gnomad ASJ exome AF: 0.0977

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.0902

GnomAD4 exome AF: 0.0990 AC: 144648 AN: 1461068 Hom.: 7704 Cov.: 31 AF XY: 0.0996 AC XY: 72382 AN XY: 726884

African (AFR) AF: 0.0621 AC: 2079 AN: 33470

American (AMR) AF: 0.0430 AC: 1924 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0974 AC: 2546 AN: 26130

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.103 AC: 8876 AN: 86244

European-Finnish (FIN) AF: 0.118 AC: 6287 AN: 53414

Middle Eastern (MID) AF: 0.130 AC: 748 AN: 5768

European-Non Finnish (NFE) AF: 0.105 AC: 116518 AN: 1111254

Other (OTH) AF: 0.0937 AC: 5656 AN: 60364

GnomAD4 genome AF: 0.0859 AC: 13076 AN: 152258 Hom.: 645 Cov.: 32 AF XY: 0.0872 AC XY: 6488 AN XY: 74420

African (AFR) AF: 0.0605 AC: 2513 AN: 41556

American (AMR) AF: 0.0602 AC: 922 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0954 AC: 331 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5180

South Asian (SAS) AF: 0.0941 AC: 454 AN: 4824

European-Finnish (FIN) AF: 0.126 AC: 1332 AN: 10594

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7218 AN: 68008

Other (OTH) AF: 0.0959 AC: 203 AN: 2116

Alfa AF: 0.0948 Hom.: 189

Bravo AF: 0.0797

Asia WGS AF: 0.0470 AC: 163 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	13
DANN	Benign	0.84
PhyloP100		0.77
PromoterAI		-0.0062	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs76857783; hg19: chr11-20621186;