Variant 11-62993625-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_004254.4(SLC22A8):c.1328A>C(p.Gln443Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000125 in 1,606,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

SLC22A8
NM_004254.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.95

Variant links:

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]

SLC22A8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A8	NM_004254.4 linkuse as main transcript	c.1328A>C	p.Gln443Pro	missense_variant, splice_region_variant	10/11	ENST00000336232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A8	ENST00000336232.7 linkuse as main transcript	c.1328A>C	p.Gln443Pro	missense_variant, splice_region_variant	10/11	1	NM_004254.4	P1	Q8TCC7-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000162

AC:

AN:

247448

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

133520

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000582

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.00000481

AC:

AN:

1453946

Hom.:

Cov.:

AF XY:

0.00000416

AC XY:

AN XY:

721818

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000899

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:

0.00

Gnomad4 OTH exome

AF:

0.0000500

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.000200

ExAC

AF:

0.00000824

AC:

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

May 27, 2022

The c.1328A>C (p.Q443P) alteration is located in exon 10 (coding exon 9) of the SLC22A8 gene. This alteration results from a A to C substitution at nucleotide position 1328, causing the glutamine (Q) at amino acid position 443 to be replaced by a proline (P). 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

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.20

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.;.;T;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.97

M_CAP

Benign

0.032

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Uncertain

-0.068

MutationAssessor

Pathogenic

3.4

M;.;.;.;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.9

D;D;D;D;D

REVEL

Uncertain

0.62

Sift

Uncertain

0.0030

D;D;D;D;D

Sift4G

Uncertain

0.021

D;D;D;D;D

Polyphen

1.0

D;.;.;.;D

Vest4

0.86

MutPred

0.84

Loss of MoRF binding (P = 0.0729);.;.;Loss of MoRF binding (P = 0.0729);Loss of MoRF binding (P = 0.0729);

MVP

0.68

MPC

1.2

ClinPred

0.94

GERP RS

5.9

Varity_R

0.96

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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