rs61736603

chr11-20601625-C-Achr11-20601625-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004211.5(SLC6A5):c.500C>A(p.Thr167Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00325 in 1,614,056 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T167T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (93 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (94 hom.)
• Consequence: SLC6A5 NM_004211.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.63

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003014952).
• BP6: Variant 11-20601625-C-A is Benign according to our data. Variant chr11-20601625-C-A is described in ClinVar as [Benign]. Clinvar id is 304012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-20601625-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A5	NM_004211.5	c.500C>A	p.Thr167Lys	missense_variant	2/16	ENST00000525748.6
SLC6A5	NM_001318369.2	c.-64C>A		5_prime_UTR_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A5	ENST00000525748.6	c.500C>A	p.Thr167Lys	missense_variant	2/16	1	NM_004211.5	P1
SLC6A5	ENST00000298923.11	c.500C>A	p.Thr167Lys	missense_variant, NMD_transcript_variant	2/15	1

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2594 AN: 152206 Hom.: 94 Cov.: 33

Gnomad AFR AF: 0.0595

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00463 AC: 1153 AN: 248834 Hom.: 32 AF XY: 0.00358 AC XY: 483 AN XY: 134876

Gnomad AFR exome AF: 0.0636

Gnomad AMR exome AF: 0.00261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000188

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00180 AC: 2638 AN: 1461732 Hom.: 94 Cov.: 35 AF XY: 0.00158 AC XY: 1149 AN XY: 727172

Gnomad4 AFR exome AF: 0.0646

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000755

Gnomad4 OTH exome AF: 0.00383

GnomAD4 genome AF: 0.0171 AC: 2601 AN: 152324 Hom.: 93 Cov.: 33 AF XY: 0.0165 AC XY: 1232 AN XY: 74480

Gnomad4 AFR AF: 0.0595

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00300 Hom.: 16

Bravo AF: 0.0196

ESP6500AA AF: 0.0626 AC: 276

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00572 AC: 695

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperekplexia 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hyperekplexia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.065	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.29
Sift	Benign	0.16	T
Sift4G	Benign	0.13	T
Polyphen		0.55	P
Vest4		0.43
MVP		0.87
MPC		0.29
ClinPred		0.045	T
GERP RS		5.4
Varity_R		0.22
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs61736603; hg19: chr11-20623171; COSMIC: COSV54229016;