Genetic Variant SLC22A9:p.Arg228Lys (chr11-63373915-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_080866.3(SLC22A9):c.683G>A(p.Arg228Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,613,524 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

SLC22A9
NM_080866.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.784

Publications

1 publications found

Variant links:

Genes affected

SLC22A9 (HGNC:16261): (solute carrier family 22 member 9) Enables anion:anion antiporter activity; short-chain fatty acid transmembrane transporter activity; and sodium-independent organic anion transmembrane transporter activity. Involved in hormone transport; short-chain fatty acid import; and sodium-independent organic anion transport. Located in basolateral plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLC22A9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015760064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A9	NM_080866.3 link	c.683G>A	p.Arg228Lys	missense_variant	Exon 4 of 10	ENST00000279178.4	NP_543142.2	Q8IVM8-1
SLC22A9	XM_017017159.3 link	c.683G>A	p.Arg228Lys	missense_variant	Exon 4 of 8		XP_016872648.1
SLC22A9	XM_047426335.1 link	c.-11G>A		5_prime_UTR_variant	Exon 2 of 8		XP_047282291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A9	ENST00000279178.4 link	c.683G>A	p.Arg228Lys	missense_variant	Exon 4 of 10	1	NM_080866.3	ENSP00000279178.3		Q8IVM8-1
SLC22A9	ENST00000536333.5 link	n.528G>A		non_coding_transcript_exon_variant	Exon 3 of 7	1		ENSP00000440206.1		Q8IVM8-2

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000519

AC:

AN:

250564

AF XY:

0.0000517

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000411

AC:

AN:

1461334

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

726962

show subpopulations

African (AFR)

AF:

0.000867

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1111724

Other (OTH)

AF:

0.000149

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000184

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.000603

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000201

Hom.:

Bravo

AF:

0.000204

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 17, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.683G>A (p.R228K) alteration is located in exon 4 (coding exon 4) of the SLC22A9 gene. This alteration results from a G to A substitution at nucleotide position 683, causing the arginine (R) at amino acid position 228 to be replaced by a lysine (K). 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

Benign

0.11

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.0040

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.063

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.32

M_CAP

Benign

0.0075

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.21

PhyloP100

-0.78

PrimateAI

Benign

0.26

PROVEAN

Benign

0.37

REVEL

Benign

0.030

Sift

Benign

1.0

Sift4G

Benign

0.81

Polyphen

0.0050

Vest4

0.028

MVP

0.14

MPC

0.013

ClinPred

0.011

GERP RS

-3.0

Varity_R

0.044

gMVP

0.14

Mutation Taster

=100/0

polymorphism

(source)

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

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11-63373915-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over