Genetic Variant NM_002555.6:c.65G>A (chr11-2903410-G-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002555.6(SLC22A18):c.65G>A(p.Arg22Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00902 in 1,613,100 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0072 ( 11 hom., cov: 33)

Exomes 𝑓: 0.0092 ( 89 hom. )

Consequence

SLC22A18
NM_002555.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.517

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:

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

SLC22A18AS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036143064).

BP6

Variant 11-2903410-G-A is Benign according to our data. Variant chr11-2903410-G-A is described in ClinVar as [Benign]. Clinvar id is 789206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A18	NM_002555.6 link	c.65G>A	p.Arg22Gln	missense_variant	Exon 2 of 11	ENST00000649076.2	NP_002546.3	Q96BI1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A18	ENST00000649076.2 link	c.65G>A	p.Arg22Gln	missense_variant	Exon 2 of 11		NM_002555.6	ENSP00000497561.1		Q96BI1

Frequencies

GnomAD3 genomes

AF:

0.00717

AC:

1091

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0153

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00968

Gnomad OTH

AF:

0.0153

GnomAD3 exomes

AF:

0.00763

AC:

1906

AN:

249946

Hom.:

AF XY:

0.00761

AC XY:

1032

AN XY:

135642

show subpopulations

Gnomad AFR exome

AF:

0.00192

Gnomad AMR exome

AF:

0.00894

Gnomad ASJ exome

AF:

0.0195

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00212

Gnomad FIN exome

AF:

0.00273

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.0113

GnomAD4 exome

AF:

0.00922

AC:

13466

AN:

1460822

Hom.:

Cov.:

AF XY:

0.00890

AC XY:

6467

AN XY:

726724

show subpopulations

Gnomad4 AFR exome

AF:

0.00164

Gnomad4 AMR exome

AF:

0.00964

Gnomad4 ASJ exome

AF:

0.0194

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00201

Gnomad4 FIN exome

AF:

0.00271

Gnomad4 NFE exome

AF:

0.0103

Gnomad4 OTH exome

AF:

0.00999

GnomAD4 genome

AF:

0.00716

AC:

1091

AN:

152278

Hom.:

Cov.:

AF XY:

0.00669

AC XY:

498

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00135

Gnomad4 AMR

AF:

0.0153

Gnomad4 ASJ

AF:

0.0190

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00273

Gnomad4 NFE

AF:

0.00968

Gnomad4 OTH

AF:

0.0152

Alfa

AF:

0.00919

Hom.:

Bravo

AF:

0.00796

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0114

AC:

ExAC

AF:

0.00747

AC:

906

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0101

EpiControl

AF:

0.00972

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 18, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

7.2

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0021

T;T;T;.;T;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.58

.;.;.;T;T;T

MetaRNN

Benign

0.0036

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;L;L;.;L;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.87

N;N;.;N;N;N

REVEL

Benign

0.088

Sift

Benign

0.11

T;T;.;T;T;T

Sift4G

Uncertain

0.041

D;D;.;T;D;T

Polyphen

0.93

P;P;P;D;P;.

Vest4

0.080

MVP

0.68

MPC

0.20

ClinPred

0.0079

GERP RS

2.3

Varity_R

0.037

gMVP

0.22

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

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