chr11-20599671-A-G

Variant names:

• chr11-20599671-A-G
• rs142828768
• NM_004211.5:c.-2A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_004211.5(SLC6A5):​c.-2A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000617 in 1,613,962 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (1 hom.)
• Consequence: SLC6A5 NM_004211.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.88
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000664 (971/1461850) while in subpopulation NFE AF = 0.000844 (939/1111996). AF 95% confidence interval is 0.000799. There are 1 homozygotes in GnomAdExome4. There are 451 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.-2A>G		5_prime_UTR	Exon 1 of 16	NP_004202.4	Q9Y345-1
	SLC6A5	NM_001318369.2		c.-565A>G		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.-2A>G		5_prime_UTR	Exon 1 of 16	ENSP00000434364.2	Q9Y345-1
	SLC6A5	ENST00000298923.11	TSL:1	n.-2A>G		non_coding_transcript_exon	Exon 1 of 15	ENSP00000298923.7	J3KNC4
	SLC6A5	ENST00000298923.11	TSL:1	n.-2A>G		5_prime_UTR	Exon 1 of 15	ENSP00000298923.7	J3KNC4

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000195 AC: 49 AN: 251474 AF XY: 0.000206

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000664 AC: 971 AN: 1461850 Hom.: 1 Cov.: 31 AF XY: 0.000620 AC XY: 451 AN XY: 727222

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000844 AC: 939 AN: 1111996

Other (OTH) AF: 0.000397 AC: 24 AN: 60396

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74310

African (AFR) AF: 0.000121 AC: 5 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68026

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000458 Hom.: 0

Bravo AF: 0.000257

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hyperekplexia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.93
PhyloP100		1.9
PromoterAI		-0.090	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs142828768; hg19: chr11-20621217;