chr11-62999835-G-A

Variant names:

• chr11-62999835-G-A
• rs45566039
• NM_004254.4:c.445C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004254.4(SLC22A8):​c.445C>T​(p.Arg149Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,553,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SLC22A8 NM_004254.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.91
• Publications: 19 publications found

Genes affected

SLC22A8 (HGNC:10972): (solute carrier family 22 member 8) This gene encodes a protein involved in the sodium-independent transport and excretion of organic anions, some of which are potentially toxic. The encoded protein is an integral membrane protein and appears to be localized to the basolateral membrane of the kidney. Multiple alternatively spliced transcript variants that encode different protein isoforms have been described for this gene. [provided by RefSeq, May 2010]

ENSG00000301851 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004254.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A8	NM_004254.4	MANE Select	c.445C>T	p.Arg149Cys	missense	Exon 4 of 11	NP_004245.2
	SLC22A8	NM_001184732.2		c.445C>T	p.Arg149Cys	missense	Exon 4 of 11	NP_001171661.1
	SLC22A8	NM_001184733.2		c.172C>T	p.Arg58Cys	missense	Exon 4 of 11	NP_001171662.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A8	ENST00000336232.7	TSL:1 MANE Select	c.445C>T	p.Arg149Cys	missense	Exon 4 of 11	ENSP00000337335.2
	SLC22A8	ENST00000430500.6	TSL:1	c.445C>T	p.Arg149Cys	missense	Exon 4 of 11	ENSP00000398548.2
	SLC22A8	ENST00000311438.12	TSL:1	c.445C>T	p.Arg149Cys	missense	Exon 3 of 9	ENSP00000311463.8

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000985 AC: 2 AN: 203062 AF XY: 0.00000912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000388

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000105

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 23 AN: 1401584 Hom.: 0 Cov.: 31 AF XY: 0.0000159 AC XY: 11 AN XY: 693624

African (AFR) AF: 0.00 AC: 0 AN: 31050

American (AMR) AF: 0.0000271 AC: 1 AN: 36936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23230

East Asian (EAS) AF: 0.00 AC: 0 AN: 36956

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5462

European-Non Finnish (NFE) AF: 0.0000194 AC: 21 AN: 1080766

Other (OTH) AF: 0.00 AC: 0 AN: 57492

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74350

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		4.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.94
MutPred		0.71		Loss of methylation at R149 (P = 0.0905)
MVP		0.76
MPC		1.3
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.79
gMVP		0.89
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs45566039; hg19: chr11-62767307; COSMIC: COSV100267647; COSMIC: COSV100267647;