11-62996135-A-G

Variant names:

• chr11-62996135-A-G
• rs11568493
• NM_004254.4:c.779T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004254.4(SLC22A8):​c.779T>C​(p.Ile260Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC22A8 NM_004254.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.73
• Publications: 0 publications found

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]

ENSG00000301851 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2987855).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A8	NM_004254.4	MANE Select	c.779T>C	p.Ile260Thr	missense	Exon 6 of 11	NP_004245.2
	SLC22A8	NM_001184732.2		c.779T>C	p.Ile260Thr	missense	Exon 6 of 11	NP_001171661.1
	SLC22A8	NM_001184733.2		c.506T>C	p.Ile169Thr	missense	Exon 6 of 11	NP_001171662.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A8	ENST00000336232.7	TSL:1 MANE Select	c.779T>C	p.Ile260Thr	missense	Exon 6 of 11	ENSP00000337335.2
	SLC22A8	ENST00000430500.6	TSL:1	c.779T>C	p.Ile260Thr	missense	Exon 6 of 11	ENSP00000398548.2
	SLC22A8	ENST00000311438.12	TSL:1	c.779T>C	p.Ile260Thr	missense	Exon 5 of 9	ENSP00000311463.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456334 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723940

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25686

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 85096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109022

Other (OTH) AF: 0.00 AC: 0 AN: 60150

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.0022	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.10	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.030	D
Polyphen		0.072	B
Vest4		0.40
MutPred		0.56		Loss of stability (P = 0.0308)
MVP		0.51
MPC		0.83
ClinPred		0.86	D
GERP RS		4.9
Varity_R		0.19
gMVP		0.50
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs11568493; hg19: chr11-62763607;