6-110425056-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_033125.4(SLC22A16):c.1551T>G(p.Ser517Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,864 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: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SLC22A16 NM_033125.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A16	NM_033125.4	c.1551T>G	p.Ser517Arg	missense_variant	8/8	ENST00000368919.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A16	ENST00000368919.8	c.1551T>G	p.Ser517Arg	missense_variant	8/8	1	NM_033125.4	P2
SLC22A16	ENST00000330550.8	c.1449T>G	p.Ser483Arg	missense_variant	10/10	1		A2
SLC22A16	ENST00000451557.5	c.*300T>G		3_prime_UTR_variant	7/7	2
SLC22A16	ENST00000460159.1	n.97T>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251232 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135794

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461864 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Nov 02, 2023

The c.1551T>G (p.S517R) alteration is located in exon 8 (coding exon 8) of the SLC22A16 gene. This alteration results from a T to G substitution at nucleotide position 1551, causing the serine (S) at amino acid position 517 to be replaced by an arginine (R). 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	0.99
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;.
Eigen	Benign	0.097
Eigen_PC	Benign	-0.069
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.86	D;D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	0.80	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.48
Sift	Benign	0.055	T;D
Sift4G	Benign	0.069	T;T
Polyphen		0.99	D;D
Vest4		0.71
MutPred		0.91		Gain of methylation at S517 (P = 0.0267);.;
MVP		0.28
MPC		0.11
ClinPred		0.87	D
GERP RS		1.4
Varity_R		0.84
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1266718486; hg19: chr6-110746259;