17-6686299-A-G

Position:

• chr17-6686299-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_177550.5(SLC13A5):​c.1615T>C​(p.Cys539Arg) variant causes a missense change involving the alteration of a non-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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77

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]

(HGNC:):

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

ACMG classification

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, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC13A5	NM_177550.5	c.1615T>C	p.Cys539Arg	missense_variant	12/12	ENST00000433363.7
SLC13A5	NM_001284509.2	c.1564T>C	p.Cys522Arg	missense_variant	12/12
SLC13A5	NM_001284510.2	c.1486T>C	p.Cys496Arg	missense_variant	11/11
SLC13A5	NM_001143838.3	c.1477T>C	p.Cys493Arg	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC13A5	ENST00000433363.7	c.1615T>C	p.Cys539Arg	missense_variant	12/12	1	NM_177550.5	P1
	ENST00000634558.1	n.511-3577A>G		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

Submissions by phenotype

Developmental and epileptic encephalopathy, 25 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 539 of the SLC13A5 protein (p.Cys539Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SLC13A5-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 639696). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC13A5 protein function. 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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.9	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.1	.;.;D;.
REVEL	Benign	0.29
Sift	Uncertain	0.0060	.;.;D;.
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		0.91	P;.;.;.
Vest4		0.63
MutPred		0.89		Gain of MoRF binding (P = 0.0153);.;.;.;
MVP		0.47
MPC		0.84
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.97
gMVP		0.97

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: rs1597651569; hg19: chr17-6589618;