11-2909210-G-A

Position:

• chr11-2909210-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002555.6(SLC22A18):​c.257G>A​(p.Arg86His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,536,602 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.0034 (17 hom., cov: 35)
  • Exomes 𝑓: 0.0025 (97 hom.)
• Consequence: SLC22A18 NM_002555.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 B:1
• Conservation: PhyloP100: -0.443

Genes affected

SLC22A18 (HGNC:10964): (solute carrier family 22 member 18) This gene is one of several tumor-suppressing subtransferable fragments located in the imprinted gene domain of 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with the Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian, and breast cancer. This gene is imprinted, with preferential expression from the maternal allele. Mutations in this gene have been found in Wilms' tumor and lung cancer. This protein may act as a transporter of organic cations, and have a role in the transport of chloroquine and quinidine-related compounds in kidney. Several alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030741394).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC22A18	NM_002555.6	c.257G>A	p.Arg86His	missense_variant	4/11	ENST00000649076.2	NP_002546.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC22A18	ENST00000649076.2	c.257G>A	p.Arg86His	missense_variant	4/11		NM_002555.6	ENSP00000497561	P1

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 521 AN: 152194 Hom.: 17 Cov.: 35

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0560

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.0144 AC: 1958 AN: 135996 Hom.: 59 AF XY: 0.0120 AC XY: 903 AN XY: 75318

Gnomad AFR exome AF: 0.000662

Gnomad AMR exome AF: 0.0428

Gnomad ASJ exome AF: 0.000642

Gnomad EAS exome AF: 0.0699

Gnomad SAS exome AF: 0.00214

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000750

Gnomad OTH exome AF: 0.00772

GnomAD4 exome AF: 0.00247 AC: 3417 AN: 1384292 Hom.: 97 Cov.: 36 AF XY: 0.00235 AC XY: 1604 AN XY: 683808

Gnomad4 AFR exome AF: 0.000260

Gnomad4 AMR exome AF: 0.0345

Gnomad4 ASJ exome AF: 0.000323

Gnomad4 EAS exome AF: 0.0462

Gnomad4 SAS exome AF: 0.00205

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000454

Gnomad4 OTH exome AF: 0.00459

GnomAD4 genome AF: 0.00343 AC: 522 AN: 152310 Hom.: 17 Cov.: 35 AF XY: 0.00395 AC XY: 294 AN XY: 74480

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.0110

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0560

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00145 Hom.: 1

Bravo AF: 0.00530

ExAC AF: 0.00795 AC: 848

Asia WGS AF: 0.0370 AC: 128 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Rhabdomyosarcoma, somatic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 31, 1998

- -

SLC22A18-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 04, 2020

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	0.078
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	2.2
DANN	Benign	0.94
DEOGEN2	Benign	0.025	T;T;T;T;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.71	.;.;.;T;T
MetaRNN	Benign	0.0031	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.98	L;L;L;L;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.82	N;N;.;N;N
REVEL	Benign	0.028
Sift	Benign	0.52	T;T;.;T;T
Sift4G	Benign	0.56	T;T;.;T;T
Polyphen		0.11	B;B;B;B;.
Vest4		0.055
MPC		0.21
ClinPred		0.0040	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.036
gMVP		0.14

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: rs78838117; hg19: chr11-2930440;