Variant 11-2909588-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002555.6(SLC22A18):c.414G>A(p.Met138Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000826 in 1,529,576 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00084 ( 2 hom. )

Consequence

SLC22A18
NM_002555.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.39

Variant links:

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]

SLC22A18 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16769215).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC22A18	NM_002555.6 linkuse as main transcript	c.414G>A	p.Met138Ile	missense_variant	5/11	ENST00000649076.2	NP_002546.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC22A18	ENST00000649076.2 linkuse as main transcript	c.414G>A	p.Met138Ile	missense_variant	5/11		NM_002555.6	ENSP00000497561	P1

Frequencies

GnomAD3 genomes

AF:

0.000677

AC:

103

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000601

AC:

AN:

124746

Hom.:

AF XY:

0.000567

AC XY:

AN XY:

68768

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000291

Gnomad ASJ exome

AF:

0.000386

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000454

Gnomad FIN exome

AF:

0.000159

Gnomad NFE exome

AF:

0.00126

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000842

AC:

1160

AN:

1377486

Hom.:

Cov.:

AF XY:

0.000874

AC XY:

594

AN XY:

679768

show subpopulations

Gnomad4 AFR exome

AF:

0.0000658

Gnomad4 AMR exome

AF:

0.000198

Gnomad4 ASJ exome

AF:

0.000161

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000381

Gnomad4 FIN exome

AF:

0.0000571

Gnomad4 NFE exome

AF:

0.00102

Gnomad4 OTH exome

AF:

0.000748

GnomAD4 genome

AF:

0.000677

AC:

103

AN:

152090

Hom.:

Cov.:

AF XY:

0.000592

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00131

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.000939

Hom.:

Bravo

AF:

0.000657

ExAC

AF:

0.000235

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2022

The c.414G>A (p.M138I) alteration is located in exon 5 (coding exon 4) of the SLC22A18 gene. This alteration results from a G to A substitution at nucleotide position 414, causing the methionine (M) at amino acid position 138 to be replaced by an isoleucine (I). 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

0.92

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;T;T;T

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.58

LIST_S2

Uncertain

0.90

.;.;.;D

M_CAP

Benign

0.066

MetaRNN

Benign

0.17

T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.8

M;M;M;M

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-2.9

D;D;.;D

REVEL

Benign

0.19

Sift

Uncertain

0.0050

D;D;.;D

Sift4G

Uncertain

0.054

T;T;.;T

Polyphen

0.98

D;D;D;D

Vest4

0.53

MutPred

0.51

Gain of catalytic residue at L143 (P = 0.0581);Gain of catalytic residue at L143 (P = 0.0581);Gain of catalytic residue at L143 (P = 0.0581);Gain of catalytic residue at L143 (P = 0.0581);

MVP

0.70

MPC

0.59

ClinPred

0.093

GERP RS

3.4

Varity_R

0.73

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over