Genetic Variant NM_004254.4:c.1346G>C (chr11-62993607-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004254.4(SLC22A8):c.1346G>C(p.Ser449Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S449N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SLC22A8
NM_004254.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.262

Publications

0 publications found

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:

ENSG00000301851 (HGNC:):

ENSG00000301851 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13364646).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC22A8	NM_004254.4	MANE Select	c.1346G>C	p.Ser449Thr	missense	Exon 10 of 11	NP_004245.2
SLC22A8	NM_001184732.2		c.1346G>C	p.Ser449Thr	missense	Exon 10 of 11	NP_001171661.1	Q8TCC7-1
SLC22A8	NM_001184733.2		c.1073G>C	p.Ser358Thr	missense	Exon 10 of 11	NP_001171662.1	Q8TCC7-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC22A8	ENST00000336232.7	TSL:1 MANE Select	c.1346G>C	p.Ser449Thr	missense	Exon 10 of 11	ENSP00000337335.2	Q8TCC7-1
SLC22A8	ENST00000430500.6	TSL:1	c.1346G>C	p.Ser449Thr	missense	Exon 10 of 11	ENSP00000398548.2	Q8TCC7-1
SLC22A8	ENST00000311438.12	TSL:1	c.1346G>C	p.Ser449Thr	missense	Exon 9 of 9	ENSP00000311463.8	H7BXN9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458402

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724888

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33412

American (AMR)

AF:

0.00

AC:

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25944

East Asian (EAS)

AF:

0.00

AC:

AN:

39636

South Asian (SAS)

AF:

0.00

AC:

AN:

86076

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109366

Other (OTH)

AF:

0.00

AC:

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

7.5

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.12

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.28

M_CAP

Benign

0.0087

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.5

PhyloP100

-0.26

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.63

REVEL

Benign

0.091

Sift

Benign

0.28

Sift4G

Benign

1.0

Polyphen

0.0090

Vest4

0.14

MutPred

0.43

Loss of MoRF binding (P = 0.1068)

MVP

0.31

MPC

0.57

ClinPred

0.15

GERP RS

3.0

Varity_R

0.10

gMVP

0.68

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over