Genetic Variant SLC15A2:p.Ala47Gly (chr3-121896440-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021082.4(SLC15A2):c.140C>G(p.Ala47Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

SLC15A2
NM_021082.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.43

Variant links:

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]

SLC15A2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19298843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC15A2	NM_021082.4 link	c.140C>G	p.Ala47Gly	missense_variant	Exon 2 of 22	ENST00000489711.6	NP_066568.3	Q16348-1
SLC15A2	NM_001145998.2 link	c.140C>G	p.Ala47Gly	missense_variant	Exon 2 of 21		NP_001139470.1	Q16348-2
SLC15A2	XM_005247722.4 link	c.140C>G	p.Ala47Gly	missense_variant	Exon 2 of 21		XP_005247779.1
SLC15A2	XM_006713736.4 link	c.140C>G	p.Ala47Gly	missense_variant	Exon 2 of 19		XP_006713799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC15A2	ENST00000489711.6 link	c.140C>G	p.Ala47Gly	missense_variant	Exon 2 of 22	1	NM_021082.4	ENSP00000417085.1	Q16348-1
SLC15A2	ENST00000295605.6 link	c.140C>G	p.Ala47Gly	missense_variant	Exon 2 of 21	2		ENSP00000295605.2	Q16348-2
SLC15A2	ENST00000469013 link	c.-47C>G		5_prime_UTR_variant	Exon 2 of 7	4		ENSP00000418704.1	C9IZ38

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251368

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0000224

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.140C>G (p.A47G) alteration is located in exon 2 (coding exon 2) of the SLC15A2 gene. This alteration results from a C to G substitution at nucleotide position 140, causing the alanine (A) at amino acid position 47 to be replaced by a glycine (G). 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

0.11

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.089

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.85

D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;L

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.055

Sift

Benign

0.18

T;T

Sift4G

Benign

0.076

T;T

Polyphen

0.0030

B;.

Vest4

0.55

MutPred

0.46

Loss of stability (P = 0.017);Loss of stability (P = 0.017);

MVP

0.63

MPC

0.077

ClinPred

0.17

GERP RS

2.7

Varity_R

0.11

gMVP

0.52

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over