11-2909224-G-A

Variant names:

• chr11-2909224-G-A
• rs749996735
• NM_002555.6:c.271G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002555.6(SLC22A18):​c.271G>A​(p.Ala91Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,386,930 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SLC22A18 NM_002555.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A18	NM_002555.6	c.271G>A	p.Ala91Thr	missense_variant	Exon 4 of 11	ENST00000649076.2	NP_002546.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A18	ENST00000649076.2	c.271G>A	p.Ala91Thr	missense_variant	Exon 4 of 11		NM_002555.6	ENSP00000497561.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1386930 Hom.: 0 Cov.: 36 AF XY: 0.00000146 AC XY: 1 AN XY: 685146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.25e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;T;T;.
Eigen	Benign	0.064
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.91	.;.;.;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.43	T;T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.9	M;M;M;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.1	D;D;.;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0040	D;D;.;D;D
Sift4G	Uncertain	0.011	D;D;.;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.39
MutPred		0.44		Gain of glycosylation at A91 (P = 0.1435);Gain of glycosylation at A91 (P = 0.1435);Gain of glycosylation at A91 (P = 0.1435);Gain of glycosylation at A91 (P = 0.1435);Gain of glycosylation at A91 (P = 0.1435);
MVP		0.83
MPC		0.67
ClinPred		0.98	D
GERP RS		3.1
Varity_R		0.70
gMVP		0.41

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: rs749996735; hg19: chr11-2930454;