11-62996072-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004254.4(SLC22A8):c.842T>C(p.Val281Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 1,614,062 control chromosomes in the GnomAD database, including 124 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.015 (58 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (66 hom.)
• Consequence: SLC22A8 NM_004254.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.872

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024286509).
• BP6: Variant 11-62996072-A-G is Benign according to our data. Variant chr11-62996072-A-G is described in ClinVar as [Benign]. Clinvar id is 710003.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0147 (2239/152224) while in subpopulation AFR AF= 0.0492 (2044/41504). AF 95% confidence interval is 0.0475. There are 58 homozygotes in gnomad4. There are 1065 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A8	NM_004254.4	c.842T>C	p.Val281Ala	missense_variant	6/11	ENST00000336232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A8	ENST00000336232.7	c.842T>C	p.Val281Ala	missense_variant	6/11	1	NM_004254.4	P1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2220 AN: 152106 Hom.: 56 Cov.: 33

Gnomad AFR AF: 0.0489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00436 AC: 1097 AN: 251336 Hom.: 24 AF XY: 0.00325 AC XY: 442 AN XY: 135824

Gnomad AFR exome AF: 0.0505

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00739

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00198 AC: 2901 AN: 1461838 Hom.: 66 Cov.: 31 AF XY: 0.00175 AC XY: 1275 AN XY: 727226

Gnomad4 AFR exome AF: 0.0497

Gnomad4 AMR exome AF: 0.00282

Gnomad4 ASJ exome AF: 0.00279

Gnomad4 EAS exome AF: 0.0162

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.00412

GnomAD4 genome AF: 0.0147 AC: 2239 AN: 152224 Hom.: 58 Cov.: 33 AF XY: 0.0143 AC XY: 1065 AN XY: 74420

Gnomad4 AFR AF: 0.0492

Gnomad4 AMR AF: 0.00582

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.0106

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00622 Hom.: 7

Bravo AF: 0.0164

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0500 AC: 220

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00524 AC: 636

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 26, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	17
Dann	Benign	0.56
DEOGEN2	Benign	0.084	T;.;.;T;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.0096	N
MetaRNN	Benign	0.0024	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.9	N;.;.;.;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	1.5	N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.95	T;T;T;T;T
Sift4G	Benign	0.56	T;T;T;T;T
Polyphen		0.0	B;.;.;.;B
Vest4		0.031
MVP		0.19
MPC		0.41
ClinPred		0.0018	T
GERP RS		5.1
Varity_R		0.043
gMVP		0.35

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: rs45438191; hg19: chr11-62763544; COSMIC: COSV100267797; COSMIC: COSV100267797;