rs2032892

chr5-36676981-G-C

Variant summary

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

The NM_004172.5(SLC1A3):c.657G>C(p.Glu219Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,614,030 control chromosomes in the GnomAD database, including 474 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (86 hom., cov: 33)
  • Exomes 𝑓: 0.012 (388 hom.)
• Consequence: SLC1A3 NM_004172.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.467

Genes affected

SLC1A3 (HGNC:10941): (solute carrier family 1 member 3) This gene encodes a member of a member of a high affinity glutamate transporter family. This gene functions in the termination of excitatory neurotransmission in central nervous system. Mutations are associated with episodic ataxia, Type 6. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2014]

SLC1A3-AS1 (HGNC:56374): (SLC1A3 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015866756).
• BP6: Variant 5-36676981-G-C is Benign according to our data. Variant chr5-36676981-G-C is described in ClinVar as [Benign]. Clinvar id is 130326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-36676981-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC1A3	NM_004172.5	c.657G>C	p.Glu219Asp	missense_variant	6/10	ENST00000265113.9
SLC1A3-AS1	XR_007058736.1	n.76-8270C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC1A3	ENST00000265113.9	c.657G>C	p.Glu219Asp	missense_variant	6/10	1	NM_004172.5	P1
SLC1A3-AS1	ENST00000510740.1	n.61-8270C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2971 AN: 152144 Hom.: 86 Cov.: 33

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0704

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00660

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0247 AC: 6215 AN: 251238 Hom.: 265 AF XY: 0.0209 AC XY: 2841 AN XY: 135782

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.0295

Gnomad EAS exome AF: 0.000653

Gnomad SAS exome AF: 0.0172

Gnomad FIN exome AF: 0.00374

Gnomad NFE exome AF: 0.00667

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0115 AC: 16880 AN: 1461768 Hom.: 388 Cov.: 31 AF XY: 0.0114 AC XY: 8266 AN XY: 727194

Gnomad4 AFR exome AF: 0.0281

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.0280

Gnomad4 EAS exome AF: 0.00149

Gnomad4 SAS exome AF: 0.0184

Gnomad4 FIN exome AF: 0.00440

Gnomad4 NFE exome AF: 0.00679

Gnomad4 OTH exome AF: 0.0137

GnomAD4 genome AF: 0.0195 AC: 2975 AN: 152262 Hom.: 86 Cov.: 33 AF XY: 0.0197 AC XY: 1467 AN XY: 74450

Gnomad4 AFR AF: 0.0292

Gnomad4 AMR AF: 0.0706

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.00660

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0100 Hom.: 15

Bravo AF: 0.0247

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.0286 AC: 126

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.0205 AC: 2491

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.00742

EpiControl AF: 0.00883

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	This variant is associated with the following publications: (PMID: 21233784, 33126486, 32819603) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 15, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Episodic ataxia type 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	13
Dann	Uncertain	0.98
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.55	T;T;T
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.82	D;D;D
PrimateAI	Uncertain	0.60	T
Sift4G	Benign	0.46	T;T;T
Polyphen		0.0010	.;B;.
Vest4		0.071
MutPred		0.22		.;Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MPC		0.41
ClinPred		0.011	T
GERP RS		-0.25
Varity_R		0.053
gMVP		0.63

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: rs2032892; hg19: chr5-36677083;