11-62995792-T-A

Position:

• chr11-62995792-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004254.4(SLC22A8):​c.913A>T​(p.Ile305Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,614,018 control chromosomes in the GnomAD database, including 57 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 0.0024 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (50 hom.)
• Consequence: SLC22A8 NM_004254.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.498

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020394623).
• BP6: Variant 11-62995792-T-A is Benign according to our data. Variant chr11-62995792-T-A is described in ClinVar as [Benign]. Clinvar id is 1232453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00236 (359/152198) while in subpopulation EAS AF= 0.0531 (274/5164). AF 95% confidence interval is 0.0479. There are 7 homozygotes in gnomad4. There are 203 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A8	NM_004254.4	c.913A>T	p.Ile305Phe	missense_variant	7/11	ENST00000336232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A8	ENST00000336232.7	c.913A>T	p.Ile305Phe	missense_variant	7/11	1	NM_004254.4	P1

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 358 AN: 152080 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000918

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0527

Gnomad SAS AF: 0.00291

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00471 AC: 1184 AN: 251356 Hom.: 30 AF XY: 0.00448 AC XY: 609 AN XY: 135830

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.0591

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00158 AC: 2308 AN: 1461820 Hom.: 50 Cov.: 30 AF XY: 0.00155 AC XY: 1129 AN XY: 727222

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.0474

Gnomad4 SAS exome AF: 0.000707

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.00328

GnomAD4 genome AF: 0.00236 AC: 359 AN: 152198 Hom.: 7 Cov.: 32 AF XY: 0.00273 AC XY: 203 AN XY: 74410

Gnomad4 AFR AF: 0.000915

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0531

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00174 Hom.: 6

Bravo AF: 0.00282

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00441 AC: 535

Asia WGS AF: 0.0260 AC: 90 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	This variant is associated with the following publications: (PMID: 23649425) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.24	T;.;.;T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.51	.;T;T;T;T
MetaRNN	Benign	0.0020	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	2.0	M;.;.;.;M
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.28	T;T;T;T;T
Sift4G	Benign	0.20	T;T;D;T;T
Polyphen		0.010	B;.;.;.;B
Vest4		0.13
MVP		0.34
MPC		0.64
ClinPred		0.0083	T
GERP RS		2.7
Varity_R		0.19
gMVP		0.65

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: rs11568482; hg19: chr11-62763264;