11-20601467-C-G

Position:

• chr11-20601467-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004211.5(SLC6A5):​c.342C>G​(p.Pro114Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00987 in 1,611,348 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (6 hom., cov: 35)
  • Exomes 𝑓: 0.010 (94 hom.)
• Consequence: SLC6A5 NM_004211.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.07

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 11-20601467-C-G is Benign according to our data. Variant chr11-20601467-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 304004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00748 (1139/152342) while in subpopulation NFE AF= 0.0126 (857/68030). AF 95% confidence interval is 0.0119. There are 6 homozygotes in gnomad4. There are 504 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A5	NM_004211.5	c.342C>G	p.Pro114Pro	synonymous_variant	2/16	ENST00000525748.6	NP_004202.4
SLC6A5	NM_001318369.2	c.-222C>G		5_prime_UTR_variant	2/15		NP_001305298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A5	ENST00000525748.6	c.342C>G	p.Pro114Pro	synonymous_variant	2/16	1	NM_004211.5	ENSP00000434364.2
SLC6A5	ENST00000298923.11	n.342C>G		non_coding_transcript_exon_variant	2/15	1		ENSP00000298923.7

Frequencies

GnomAD3 genomes AF: 0.00748 AC: 1139 AN: 152224 Hom.: 6 Cov.: 35

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00405

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00692 AC: 1669 AN: 241166 Hom.: 11 AF XY: 0.00689 AC XY: 905 AN XY: 131318

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00225

Gnomad ASJ exome AF: 0.00153

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00117

Gnomad FIN exome AF: 0.0101

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.00560

GnomAD4 exome AF: 0.0101 AC: 14760 AN: 1459006 Hom.: 94 Cov.: 70 AF XY: 0.00987 AC XY: 7161 AN XY: 725654

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.00177

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00160

Gnomad4 FIN exome AF: 0.00969

Gnomad4 NFE exome AF: 0.0121

Gnomad4 OTH exome AF: 0.00784

GnomAD4 genome AF: 0.00748 AC: 1139 AN: 152342 Hom.: 6 Cov.: 35 AF XY: 0.00677 AC XY: 504 AN XY: 74496

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0102

Gnomad4 NFE AF: 0.0126

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00694 Hom.: 0

Bravo AF: 0.00647

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperekplexia 3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	SLC6A5: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hyperekplexia Benign:1

Likely 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
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.23
DANN	Benign	0.66

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: rs61736605; hg19: chr11-20623013;