chr17-6686269-G-A

Position:

chr17-6686269-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_177550.5(SLC13A5):c.1645C>T(p.Arg549Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R549Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

SLC13A5
NM_177550.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.737

Variant links:

Genes affected

SLC13A5 (HGNC:23089): (solute carrier family 13 member 5) This gene encodes a protein belonging to the solute carrier family 13 group of proteins. This family member is a sodium-dependent citrate cotransporter that may regulate metabolic processes. Mutations in this gene cause early infantile epileptic encephalopathy 25. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2014]

SLC13A5 links:

(HGNC:):

links:

C17orf100 (HGNC:34494): (chromosome 17 open reading frame 100)

C17orf100 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC13A5	NM_177550.5 linkuse as main transcript	c.1645C>T	p.Arg549Trp	missense_variant	12/12	ENST00000433363.7
SLC13A5	NM_001284509.2 linkuse as main transcript	c.1594C>T	p.Arg532Trp	missense_variant	12/12
SLC13A5	NM_001284510.2 linkuse as main transcript	c.1516C>T	p.Arg506Trp	missense_variant	11/11
SLC13A5	NM_001143838.3 linkuse as main transcript	c.1507C>T	p.Arg503Trp	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC13A5	ENST00000433363.7 linkuse as main transcript	c.1645C>T	p.Arg549Trp	missense_variant	12/12	1	NM_177550.5	P1	Q86YT5-1
	ENST00000634558.1 linkuse as main transcript	n.511-3607G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250676

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135552

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000443

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 25

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2022

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 549 of the SLC13A5 protein (p.Arg549Trp). This variant is present in population databases (rs770090939, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SLC13A5-related conditions. ClinVar contains an entry for this variant (Variation ID: 951028). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.49

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.18

T;.;.;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.18

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.46

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;.;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.4

.;.;N;.

REVEL

Benign

0.12

Sift

Benign

0.19

.;.;T;.

Sift4G

Benign

0.19

T;T;T;T

Polyphen

0.14

B;.;.;.

Vest4

0.50

MutPred

0.69

Loss of methylation at R549 (P = 0.0223);.;.;.;

MVP

0.44

MPC

0.31

ClinPred

0.18

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over