5-151316858-C-T

Position:

• chr5-151316858-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_181776.3(SLC36A2):​c.1411G>A​(p.Asp471Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000667 in 1,613,586 control chromosomes in the GnomAD database, including 8 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00066 (8 hom.)
• Consequence: SLC36A2 NM_181776.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.126

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005772382).
• BP6: Variant 5-151316858-C-T is Benign according to our data. Variant chr5-151316858-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 788353.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00066 (965/1461616) while in subpopulation MID AF= 0.0189 (109/5762). AF 95% confidence interval is 0.016. There are 8 homozygotes in gnomad4_exome. There are 468 alleles in male gnomad4_exome subpopulation. Median coverage is 45. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC36A2	NM_181776.3	c.1411G>A	p.Asp471Asn	missense_variant	10/10	ENST00000335244.9	NP_861441.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC36A2	ENST00000335244.9	c.1411G>A	p.Asp471Asn	missense_variant	10/10	1	NM_181776.3	ENSP00000334223.4

Frequencies

GnomAD3 genomes AF: 0.000731 AC: 111 AN: 151860 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000994 AC: 250 AN: 251484 Hom.: 0 AF XY: 0.000986 AC XY: 134 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.0127

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000580

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000660 AC: 965 AN: 1461616 Hom.: 8 Cov.: 45 AF XY: 0.000644 AC XY: 468 AN XY: 727102

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000296

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.000730 AC: 111 AN: 151970 Hom.: 0 Cov.: 31 AF XY: 0.000646 AC XY: 48 AN XY: 74274

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.000910

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000857 AC: 104

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 05, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

SLC36A2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.89
DANN	Benign	0.41
DEOGEN2	Benign	0.00063	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.17	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.045
Sift	Benign	0.82	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.032
MVP		0.048
MPC		0.13
ClinPred		0.012	T
GERP RS		-3.5
Varity_R		0.027
gMVP		0.19

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: rs140682366; hg19: chr5-150696419;