3-121915682-T-C

Variant names:

• chr3-121915682-T-C
• rs1709881031
• NM_021082.4:c.686T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021082.4(SLC15A2):​c.686T>C​(p.Val229Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC15A2 NM_021082.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.25

Genes affected

SLC15A2 (HGNC:10921): (solute carrier family 15 member 2) The mammalian kidney expresses a proton-coupled peptide transporter that is responsible for the absorption of small peptides, as well as beta-lactam antibiotics and other peptide-like drugs, from the tubular filtrate. This transporter, SLC15A2, belongs to the same gene family as SLC15A1 (MIM 600544), the proton-coupled peptide transporter found in the small intestine (Liu et al, 1995 [PubMed 7756356]).[supplied by OMIM, Feb 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3446886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC15A2	NM_021082.4	c.686T>C	p.Val229Ala	missense_variant	Exon 7 of 22	ENST00000489711.6	NP_066568.3
SLC15A2	NM_001145998.2	c.593T>C	p.Val198Ala	missense_variant	Exon 6 of 21		NP_001139470.1
SLC15A2	XM_005247722.4	c.686T>C	p.Val229Ala	missense_variant	Exon 7 of 21		XP_005247779.1
SLC15A2	XM_006713736.4	c.686T>C	p.Val229Ala	missense_variant	Exon 7 of 19		XP_006713799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC15A2	ENST00000489711.6	c.686T>C	p.Val229Ala	missense_variant	Exon 7 of 22	1	NM_021082.4	ENSP00000417085.1
SLC15A2	ENST00000295605.6	c.593T>C	p.Val198Ala	missense_variant	Exon 6 of 21	2		ENSP00000295605.2
SLC15A2	ENST00000489886.1	n.274T>C		non_coding_transcript_exon_variant	Exon 3 of 6	5
SLC15A2	ENST00000469013.1	c.*43T>C		downstream_gene_variant		4		ENSP00000418704.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460546 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726678

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.686T>C (p.V229A) alteration is located in exon 7 (coding exon 7) of the SLC15A2 gene. This alteration results from a T to C substitution at nucleotide position 686, causing the valine (V) at amino acid position 229 to be replaced by an alanine (A). 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	0.13
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	-0.092
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.21
Sift	Benign	0.43	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.035	B;.
Vest4		0.37
MutPred		0.75		Loss of stability (P = 0.0548);.;
MVP		0.61
MPC		0.099
ClinPred		0.57	D
GERP RS		5.8
Varity_R		0.12
gMVP		0.62

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: rs1709881031; hg19: chr3-121634529;