rs2248829

chr1-44002563-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001024845.3(SLC6A9):c.807C>T(p.Asp269=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0902 in 1,613,730 control chromosomes in the GnomAD database, including 8,845 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2030 hom., cov: 32)
  • Exomes 𝑓: 0.085 (6815 hom.)
• Consequence: SLC6A9 NM_001024845.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.26

Genes affected

SLC6A9 (HGNC:11056): (solute carrier family 6 member 9) The amino acid glycine acts as an inhibitory neurotransmitter in the central nervous system. The protein encoded by this gene is one of two transporters that stop glycine signaling by removing it from the synaptic cleft. [provided by RefSeq, Jun 2016]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 1-44002563-G-A is Benign according to our data. Variant chr1-44002563-G-A is described in ClinVar as [Benign]. Clinvar id is 1169776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A9	NM_001024845.3	c.807C>T	p.Asp269=	synonymous_variant	7/14	ENST00000372310.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A9	ENST00000372310.8	c.807C>T	p.Asp269=	synonymous_variant	7/14	5	NM_001024845.3	P1

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20880 AN: 151918 Hom.: 2024 Cov.: 32

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.0720

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.0671

Gnomad OTH AF: 0.128

GnomAD3 exomes AF: 0.112 AC: 28059 AN: 251478 Hom.: 1987 AF XY: 0.106 AC XY: 14457 AN XY: 135914

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.0719

Gnomad EAS exome AF: 0.153

Gnomad SAS exome AF: 0.114

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.0713

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.0853 AC: 124678 AN: 1461692 Hom.: 6815 Cov.: 33 AF XY: 0.0850 AC XY: 61808 AN XY: 727162

Gnomad4 AFR exome AF: 0.276

Gnomad4 AMR exome AF: 0.153

Gnomad4 ASJ exome AF: 0.0723

Gnomad4 EAS exome AF: 0.199

Gnomad4 SAS exome AF: 0.115

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.0684

Gnomad4 OTH exome AF: 0.0982

GnomAD4 genome AF: 0.138 AC: 20923 AN: 152038 Hom.: 2030 Cov.: 32 AF XY: 0.139 AC XY: 10326 AN XY: 74344

Gnomad4 AFR AF: 0.269

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.0720

Gnomad4 EAS AF: 0.163

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.0671

Gnomad4 OTH AF: 0.127

Alfa AF: 0.0853 Hom.: 1339

Bravo AF: 0.144

Asia WGS AF: 0.134 AC: 465 AN: 3478

EpiCase AF: 0.0671

EpiControl AF: 0.0689

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SLC6A9-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 22, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

- -

Atypical glycine encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.65
Dann	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2248829; hg19: chr1-44468235; COSMIC: COSV62211607;