rs56224509

Positions:

• chr17-6695776-G-A
• chr17-6695776-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_177550.5(SLC13A5):​c.1005C>T​(p.Pro335Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0816 in 1,614,094 control chromosomes in the GnomAD database, including 6,061 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (394 hom., cov: 32)
  • Exomes 𝑓: 0.083 (5667 hom.)
• Consequence: SLC13A5 NM_177550.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.94

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 17-6695776-G-A is Benign according to our data. Variant chr17-6695776-G-A is described in ClinVar as [Benign]. Clinvar id is 380899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.94 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0918 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC13A5	NM_177550.5	c.1005C>T	p.Pro335Pro	synonymous_variant	7/12	ENST00000433363.7	NP_808218.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC13A5	ENST00000433363.7	c.1005C>T	p.Pro335Pro	synonymous_variant	7/12	1	NM_177550.5	ENSP00000406220.2

Frequencies

GnomAD3 genomes AF: 0.0652 AC: 9923 AN: 152098 Hom.: 394 Cov.: 32

Gnomad AFR AF: 0.0350

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0517

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0390

Gnomad FIN AF: 0.0849

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0937

Gnomad OTH AF: 0.0603

GnomAD3 exomes AF: 0.0615 AC: 15458 AN: 251296 Hom.: 613 AF XY: 0.0617 AC XY: 8387 AN XY: 135830

Gnomad AFR exome AF: 0.0327

Gnomad AMR exome AF: 0.0328

Gnomad ASJ exome AF: 0.0128

Gnomad EAS exome AF: 0.00359

Gnomad SAS exome AF: 0.0371

Gnomad FIN exome AF: 0.0845

Gnomad NFE exome AF: 0.0903

Gnomad OTH exome AF: 0.0613

GnomAD4 exome AF: 0.0833 AC: 121810 AN: 1461878 Hom.: 5667 Cov.: 31 AF XY: 0.0818 AC XY: 59457 AN XY: 727240

Gnomad4 AFR exome AF: 0.0295

Gnomad4 AMR exome AF: 0.0340

Gnomad4 ASJ exome AF: 0.0137

Gnomad4 EAS exome AF: 0.00758

Gnomad4 SAS exome AF: 0.0370

Gnomad4 FIN exome AF: 0.0891

Gnomad4 NFE exome AF: 0.0953

Gnomad4 OTH exome AF: 0.0765

GnomAD4 genome AF: 0.0652 AC: 9924 AN: 152216 Hom.: 394 Cov.: 32 AF XY: 0.0626 AC XY: 4662 AN XY: 74424

Gnomad4 AFR AF: 0.0350

Gnomad4 AMR AF: 0.0516

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0392

Gnomad4 FIN AF: 0.0849

Gnomad4 NFE AF: 0.0937

Gnomad4 OTH AF: 0.0592

Alfa AF: 0.0646 Hom.: 197

Bravo AF: 0.0593

Asia WGS AF: 0.0350 AC: 123 AN: 3478

EpiCase AF: 0.0808

EpiControl AF: 0.0775

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 25 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 12, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.68
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs56224509; hg19: chr17-6599095; COSMIC: COSV53423325; COSMIC: COSV53423325;