chr17-6686308-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_177550.5(SLC13A5):​c.1606G>A​(p.Gly536Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SLC13A5
NM_177550.5 missense

Scores

8
8
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57
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]
C17orf100 (HGNC:34494): (chromosome 17 open reading frame 100)

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC13A5NM_177550.5 linkuse as main transcriptc.1606G>A p.Gly536Arg missense_variant 12/12 ENST00000433363.7
SLC13A5NM_001284509.2 linkuse as main transcriptc.1555G>A p.Gly519Arg missense_variant 12/12
SLC13A5NM_001284510.2 linkuse as main transcriptc.1477G>A p.Gly493Arg missense_variant 11/11
SLC13A5NM_001143838.3 linkuse as main transcriptc.1468G>A p.Gly490Arg missense_variant 11/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC13A5ENST00000433363.7 linkuse as main transcriptc.1606G>A p.Gly536Arg missense_variant 12/121 NM_177550.5 P1Q86YT5-1
ENST00000634558.1 linkuse as main transcriptn.511-3568C>T intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

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 submitterclinical testingInvitaeJul 23, 2022This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with SLC13A5-related conditions. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 536 of the SLC13A5 protein (p.Gly536Arg). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.33
T;.;.;.
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.94
D;D;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.97
D;D;D;D
MetaSVM
Benign
-0.99
T
MutationAssessor
Pathogenic
4.0
H;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.66
T
PROVEAN
Pathogenic
-7.2
.;.;D;.
REVEL
Uncertain
0.41
Sift
Uncertain
0.0010
.;.;D;.
Sift4G
Uncertain
0.0040
D;D;D;D
Polyphen
1.0
D;.;.;.
Vest4
0.77
MutPred
0.91
Gain of MoRF binding (P = 0.0214);.;.;.;
MVP
0.54
MPC
1.0
ClinPred
1.0
D
GERP RS
4.2
Varity_R
0.96
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.50
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.50
Position offset: 30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-6589627; API