rs77010315

Positions:

• chr5-151343594-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_181776.3(SLC36A2):​c.260G>T​(p.Gly87Val) variant causes a missense change. The variant allele was found at a frequency of 0.0105 in 1,613,846 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0086 (14 hom., cov: 32)
  • Exomes 𝑓: 0.011 (105 hom.)
• Consequence: SLC36A2 NM_181776.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3 O:2
• Conservation: PhyloP100: 7.18

Genes affected

SLC36A2 (HGNC:18762): (solute carrier family 36 member 2) This gene encodes a pH-dependent proton-coupled amino acid transporter that belongs to the amino acid auxin permease 1 protein family. The encoded protein primarily transports small amino acids such as glycine, alanine and proline. Mutations in this gene are associated with iminoglycinuria and hyperglycinuria. [provided by RefSeq, Sep 2010]

SLC36A2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012553453).
• BS2: High Homozygotes in GnomAd4 at 14 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC36A2	NM_181776.3	c.260G>T	p.Gly87Val	missense_variant	3/10	ENST00000335244.9	NP_861441.2
SLC36A2	XM_005268377.5	c.260G>T	p.Gly87Val	missense_variant	3/10		XP_005268434.1
SLC36A2	XM_017009083.3	c.260G>T	p.Gly87Val	missense_variant	3/8		XP_016864572.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC36A2	ENST00000335244.9	c.260G>T	p.Gly87Val	missense_variant	3/10	1	NM_181776.3	ENSP00000334223.4

Frequencies

GnomAD3 genomes AF: 0.00861 AC: 1309 AN: 151992 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00734

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00548

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00935 AC: 2350 AN: 251320 Hom.: 22 AF XY: 0.00976 AC XY: 1325 AN XY: 135812

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00524

Gnomad ASJ exome AF: 0.0410

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00405

Gnomad FIN exome AF: 0.00522

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0107 AC: 15676 AN: 1461736 Hom.: 105 Cov.: 32 AF XY: 0.0108 AC XY: 7856 AN XY: 727184

Gnomad4 AFR exome AF: 0.00200

Gnomad4 AMR exome AF: 0.00521

Gnomad4 ASJ exome AF: 0.0439

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00385

Gnomad4 FIN exome AF: 0.00502

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.00859 AC: 1306 AN: 152110 Hom.: 14 Cov.: 32 AF XY: 0.00888 AC XY: 660 AN XY: 74334

Gnomad4 AFR AF: 0.00227

Gnomad4 AMR AF: 0.00733

Gnomad4 ASJ AF: 0.0383

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00333

Gnomad4 FIN AF: 0.00548

Gnomad4 NFE AF: 0.0129

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.0126 Hom.: 28

Bravo AF: 0.00827

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0135 AC: 52

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0129 AC: 111

ExAC AF: 0.00881 AC: 1070

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0148

EpiControl AF: 0.0161

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperglycinuria Uncertain:1 Benign:1 Other:1

Affects, no assertion criteria provided	literature only	OMIM	Dec 01, 2008	- -
Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_181776.2:c.260G>T in the SLC36A2 gene has an allele frequency of 0.041 in Ashkenazi Jewish subpopulation in the gnomAD database, including 24 homozygous occurrences. Broer et al. reported this variant in a patient with iminoglycinuria . However, iminoglycinuria was only observed when homozygous SLC36A2 G87V was combined with SLC6A20 T199M (PMID: 19033659). Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, MutationAssessor, MutationTaster, PrimateAI and SIFT. Taken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS1; BS2; PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	SLC36A2: BS1, BS2 -

Iminoglycinuria Other:1

Affects, no assertion criteria provided

literature only

OMIM

Dec 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	4.1	H;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-8.2	D;D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.99
MVP		0.39
MPC		0.67
ClinPred		0.11	T
GERP RS		4.5
Varity_R		0.97
gMVP		0.72

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: rs77010315; hg19: chr5-150723155; COSMIC: COSV58865765;