20-4857181-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_005116.6(SLC23A2):c.1744C>T(p.Arg582Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,607,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SLC23A2 NM_005116.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

Genes affected

SLC23A2 (HGNC:10973): (solute carrier family 23 member 2) The absorption of vitamin C into the body and its distribution to organs requires two sodium-dependent vitamin C transporters. This gene encodes one of the two required transporters and the encoded protein accounts for tissue-specific uptake of vitamin C. Previously, this gene had an official symbol of SLC23A1. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SLC23A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.19224057).
• BS2: High AC in GnomAd at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC23A2	NM_005116.6	c.1744C>T	p.Arg582Trp	missense_variant	17/17	ENST00000338244.6
SLC23A2	NM_203327.2	c.1744C>T	p.Arg582Trp	missense_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC23A2	ENST00000338244.6	c.1744C>T	p.Arg582Trp	missense_variant	17/17	1	NM_005116.6	P1
SLC23A2	ENST00000379333.5	c.1744C>T	p.Arg582Trp	missense_variant	17/17	1		P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151992 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000897 AC: 22 AN: 245262 Hom.: 0 AF XY: 0.0000754 AC XY: 10 AN XY: 132622

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000586

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000164

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000116 AC: 169 AN: 1455484 Hom.: 0 Cov.: 31 AF XY: 0.000105 AC XY: 76 AN XY: 723456

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000451

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74350

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000117 Hom.: 0

Bravo AF: 0.000155

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000906 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2023

The c.1744C>T (p.R582W) alteration is located in exon 17 (coding exon 15) of the SLC23A2 gene. This alteration results from a C to T substitution at nucleotide position 1744, causing the arginine (R) at amino acid position 582 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.27
Sift	Benign	0.092	T;T
Sift4G	Uncertain	0.037	D;D
Polyphen		0.99	D;D
Vest4		0.42
MVP		0.13
MPC		1.2
ClinPred		0.66	D
GERP RS		-7.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs139545711; hg19: chr20-4837827;