rs1048046

Positions:

• chr11-2903361-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_002555.6(SLC22A18):​c.16G>A​(p.Ala6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,612,492 control chromosomes in the GnomAD database, including 27,823 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.20 (3441 hom., cov: 33)
  • Exomes 𝑓: 0.18 (24382 hom.)
• Consequence: SLC22A18 NM_002555.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.474

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]

SLC22A18AS (HGNC:10965): (SLC22A18 antisense RNA)

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015569568).
• BP6: Variant 11-2903361-G-A is Benign according to our data. Variant chr11-2903361-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC22A18	NM_002555.6	c.16G>A	p.Ala6Thr	missense_variant	2/11	ENST00000649076.2	NP_002546.3
SLC22A18AS	NR_169305.1	n.117+98C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC22A18	ENST00000649076.2	c.16G>A	p.Ala6Thr	missense_variant	2/11		NM_002555.6	ENSP00000497561	P1
SLC22A18AS	ENST00000702349.1	n.355+98C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30178 AN: 151926 Hom.: 3432 Cov.: 33

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.00290

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.177

GnomAD3 exomes AF: 0.172 AC: 42833 AN: 249634 Hom.: 4429 AF XY: 0.173 AC XY: 23461 AN XY: 135398

Gnomad AFR exome AF: 0.276

Gnomad AMR exome AF: 0.0859

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.00152

Gnomad SAS exome AF: 0.188

Gnomad FIN exome AF: 0.306

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.176 AC: 256728 AN: 1460448 Hom.: 24382 Cov.: 32 AF XY: 0.177 AC XY: 128275 AN XY: 726522

Gnomad4 AFR exome AF: 0.280

Gnomad4 AMR exome AF: 0.0920

Gnomad4 ASJ exome AF: 0.165

Gnomad4 EAS exome AF: 0.00123

Gnomad4 SAS exome AF: 0.184

Gnomad4 FIN exome AF: 0.302

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.199 AC: 30213 AN: 152044 Hom.: 3441 Cov.: 33 AF XY: 0.201 AC XY: 14974 AN XY: 74324

Gnomad4 AFR AF: 0.265

Gnomad4 AMR AF: 0.120

Gnomad4 ASJ AF: 0.159

Gnomad4 EAS AF: 0.00291

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.307

Gnomad4 NFE AF: 0.178

Gnomad4 OTH AF: 0.175

Alfa AF: 0.182 Hom.: 2355

Bravo AF: 0.188

TwinsUK AF: 0.170 AC: 631

ALSPAC AF: 0.181 AC: 699

ESP6500AA AF: 0.264 AC: 1163

ESP6500EA AF: 0.180 AC: 1545

ExAC AF: 0.176 AC: 21406

Asia WGS AF: 0.113 AC: 395 AN: 3478

EpiCase AF: 0.174

EpiControl AF: 0.172

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.00063	T;T;T;.;T;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.52	.;.;.;T;T;T
MetaRNN	Benign	0.016	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;M;.;M;.
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.020	N;N;.;N;N;N
REVEL	Benign	0.048
Sift	Benign	0.15	T;T;.;D;T;T
Sift4G	Pathogenic	0.0	D;D;.;D;D;D
Polyphen		0.028	B;B;B;B;B;.
Vest4		0.032
MPC		0.17
ClinPred		0.0056	T
GERP RS		0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.39

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: rs1048046; hg19: chr11-2924591; COSMIC: COSV56539462; COSMIC: COSV56539462;