NM_004172.5:c.657G>C

Variant names:

• chr5-36676981-G-C
• rs2032892
• NM_004172.5:c.657G>C

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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:7
• Conservation: PhyloP100: 0.467
• Publications: 26 publications found

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

Our verdict: Benign. The variant received -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.
• 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 rank	MANE	Protein	UniProt
SLC1A3	NM_004172.5	c.657G>C	p.Glu219Asp	missense_variant	Exon 6 of 10	ENST00000265113.9	NP_004163.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC1A3	ENST00000265113.9	c.657G>C	p.Glu219Asp	missense_variant	Exon 6 of 10	1	NM_004172.5	ENSP00000265113.4

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

GnomAD2 exomes AF: 0.0247 AC: 6215 AN: 251238 AF XY: 0.0209

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 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

African (AFR) AF: 0.0281 AC: 941 AN: 33468

American (AMR) AF: 0.107 AC: 4788 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 731 AN: 26136

East Asian (EAS) AF: 0.00149 AC: 59 AN: 39696

South Asian (SAS) AF: 0.0184 AC: 1587 AN: 86256

European-Finnish (FIN) AF: 0.00440 AC: 235 AN: 53406

Middle Eastern (MID) AF: 0.0288 AC: 166 AN: 5768

European-Non Finnish (NFE) AF: 0.00679 AC: 7546 AN: 1111932

Other (OTH) AF: 0.0137 AC: 827 AN: 60394

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

African (AFR) AF: 0.0292 AC: 1211 AN: 41540

American (AMR) AF: 0.0706 AC: 1080 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3472

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5184

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4822

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00660 AC: 449 AN: 68012

Other (OTH) AF: 0.0180 AC: 38 AN: 2114

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Jul 15, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21233784, 33126486, 32819603) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

May 01, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Episodic ataxia type 6 Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
DEOGEN2	Benign	0.16	.;T;.
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
MutationAssessor	Benign	0.0	.;N;N
PhyloP100		0.47
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.46	.;N;N
REVEL	Benign	0.037
Sift	Benign	0.27	.;T;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
PromoterAI		0.061	Neutral
Varity_R		0.053
gMVP		0.63
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2032892; hg19: chr5-36677083;