6-110431214-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_033125.4(SLC22A16):c.1478C>T(p.Pro493Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SLC22A16 NM_033125.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.85

Genes affected

SLC22A16 (HGNC:20302): (solute carrier family 22 member 16) This gene encodes a member of the organic zwitterion transporter protein family which transports carnitine. The encoded protein has also been shown to transport anticancer drugs like bleomycin (PMID: 20037140) successful treatment has been correlated with the level of activity of this transporter in tumor cells. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A16	NM_033125.4	c.1478C>T	p.Pro493Leu	missense_variant	7/8	ENST00000368919.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A16	ENST00000368919.8	c.1478C>T	p.Pro493Leu	missense_variant	7/8	1	NM_033125.4	P2
SLC22A16	ENST00000330550.8	c.1376C>T	p.Pro459Leu	missense_variant	9/10	1		A2
SLC22A16	ENST00000451557.5	c.1229C>T	p.Pro410Leu	missense_variant	6/7	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249958 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135234

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000472

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461428 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727014

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2024

The c.1478C>T (p.P493L) alteration is located in exon 7 (coding exon 7) of the SLC22A16 gene. This alteration results from a C to T substitution at nucleotide position 1478, causing the proline (P) at amino acid position 493 to be replaced by a leucine (L). 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	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.22	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-9.1	D;D;D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.95, 0.95
MVP		0.34
MPC		0.12
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.79
gMVP		0.94

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: rs201591965; hg19: chr6-110752417; COSMIC: COSV57930755;