15-45264020-G-A

Variant names:

• chr15-45264020-G-A
• rs371217234
• NM_004212.4:c.586G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004212.4(SLC28A2):​c.586G>A​(p.Ala196Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000059 in 1,457,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: SLC28A2 NM_004212.4 missense, splice_region
• Scores: Splicing: ADA: 0.9525
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.56

Genes affected

SLC28A2 (HGNC:11002): (solute carrier family 28 member 2) Enables neurotransmitter transmembrane transporter activity and nucleoside transmembrane transporter activity. Involved in several processes, including nucleoside transport; purine nucleobase transmembrane transport; and pyrimidine-containing compound transmembrane transport. Predicted to be located in membrane. Predicted to be part of brush border membrane; coated vesicle; and vesicle membrane. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLC28A2-AS1 (HGNC:55417): (SLC28A2 antisense RNA 1)

ACMG classification

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=0.18800512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC28A2	NM_004212.4	c.586G>A	p.Ala196Thr	missense_variant, splice_region_variant	Exon 6 of 18	ENST00000347644.8	NP_004203.2
SLC28A2-AS1	NR_120335.1	n.27-8022C>T		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC28A2	ENST00000347644.8	c.586G>A	p.Ala196Thr	missense_variant, splice_region_variant	Exon 6 of 18	1	NM_004212.4	ENSP00000315006.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000925 AC: 23 AN: 248650 Hom.: 1 AF XY: 0.000149 AC XY: 20 AN XY: 134366

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000702

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000590 AC: 86 AN: 1457256 Hom.: 0 Cov.: 31 AF XY: 0.0000621 AC XY: 45 AN XY: 724410

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000472

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000124 AC: 15

EpiCase AF: 0.0000549

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.586G>A (p.A196T) alteration is located in exon 6 (coding exon 5) of the SLC28A2 gene. This alteration results from a G to A substitution at nucleotide position 586, causing the alanine (A) at amino acid position 196 to be replaced by a threonine (T). 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	0.087
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	D;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Pathogenic	4.0	H;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.22
Sift	Benign	0.11	T;D
Sift4G	Benign	0.30	T;D
Polyphen		1.0	D;.
Vest4		0.46
MVP		0.40
MPC		0.23
ClinPred		0.55	D
GERP RS		5.8
Varity_R		0.48
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.76
SpliceAI score (max)		0.010		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: rs371217234; hg19: chr15-45556218; COSMIC: COSV61663890;