11-2909588-G-A

Variant names:

• chr11-2909588-G-A
• rs779308316
• NM_002555.6:c.414G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39

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 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 rank	MANE	Protein	UniProt
SLC22A18	NM_002555.6	c.414G>A	p.Met138Ile	missense_variant	Exon 5 of 11	ENST00000649076.2	NP_002546.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A18	ENST00000649076.2	c.414G>A	p.Met138Ile	missense_variant	Exon 5 of 11		NM_002555.6	ENSP00000497561.1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152090 Hom.: 0 Cov.: 33

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: 75 AN: 124746 Hom.: 0 AF XY: 0.000567 AC XY: 39 AN XY: 68768

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.: 2 Cov.: 35 AF XY: 0.000874 AC XY: 594 AN XY: 679768

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.: 0 Cov.: 33 AF XY: 0.000592 AC XY: 44 AN XY: 74306

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.: 0

Bravo AF: 0.000657

ExAC AF: 0.000235 AC: 17

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
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	D
LIST_S2	Uncertain	0.90	.;.;.;D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.8	M;M;M;M
PrimateAI	Pathogenic	0.90	D
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	T
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

Other links and lift over

dbSNP: rs779308316; hg19: chr11-2930818;