17-6686268-C-G

Variant names:

• chr17-6686268-C-G
• rs373799811
• NM_177550.5:c.1646G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_177550.5(SLC13A5):​c.1646G>C​(p.Arg549Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC13A5 NM_177550.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.369
• Publications: 0 publications found

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]

ENSG00000290366 (HGNC:):

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177550.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC13A5	NM_177550.5	MANE Select	c.1646G>C	p.Arg549Pro	missense	Exon 12 of 12	NP_808218.1	Q86YT5-1
	SLC13A5	NM_001284509.2		c.1595G>C	p.Arg532Pro	missense	Exon 12 of 12	NP_001271438.1	Q86YT5-3
	SLC13A5	NM_001284510.2		c.1517G>C	p.Arg506Pro	missense	Exon 11 of 11	NP_001271439.1	Q86YT5-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC13A5	ENST00000433363.7	TSL:1 MANE Select	c.1646G>C	p.Arg549Pro	missense	Exon 12 of 12	ENSP00000406220.2	Q86YT5-1
	SLC13A5	ENST00000573648.5	TSL:1	c.1508G>C	p.Arg503Pro	missense	Exon 11 of 11	ENSP00000459372.1	Q86YT5-2
	SLC13A5	ENST00000898130.1		c.1634G>C	p.Arg545Pro	missense	Exon 12 of 12	ENSP00000568189.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.055
Eigen_PC	Benign	-0.083
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.73	N
PhyloP100		0.37
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.21
Sift	Benign	0.20	T
Sift4G	Benign	0.20	T
Polyphen		0.90	P
Vest4		0.58
MutPred		0.74		Loss of methylation at R549 (P = 0.0223)
MVP		0.30
MPC		1.0
ClinPred		0.92	D
GERP RS		1.9
Varity_R		0.74
gMVP		0.90
Mutation Taster		=69/31	polymorphism

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: rs373799811; hg19: chr17-6589587;