SLC22A6 p.Arg454Pro

Variant names:

• chr11-62977388-C-G
• rs770486712
• NM_153276.3:c.1362-1G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-62977388-C-G
• chr11-62977387-CC-AG
• chr11-62977387-CC-GG
• chr11-62977387-CC-TG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_153276.3(SLC22A6):​c.1362-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC22A6 NM_153276.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.82
• Publications: 0 publications found

Genes affected

SLC22A6 (HGNC:10970): (solute carrier family 22 member 6) The protein encoded by this gene is involved in the sodium-dependent transport and excretion of organic anions, some of which are potentially toxic. The encoded protein is an integral membrane protein and may be localized to the basolateral membrane. Four transcript variants encoding four different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ENSG00000301851 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.123411976 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.4, offset of 4, new splice context is: gctgcgggccctgcacgcAGaca. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153276.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A6	NM_153276.3	MANE Select	c.1362-1G>C		splice_acceptor intron	N/A	NP_695008.1	Q4U2R8-2
	SLC22A6	NM_004790.5		c.1362-1G>C		splice_acceptor intron	N/A	NP_004781.2
	SLC22A6	NM_153278.3		c.1362-133G>C		intron	N/A	NP_695010.1	Q4U2R8-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A6	ENST00000360421.9	TSL:1 MANE Select	c.1362-1G>C		splice_acceptor intron	N/A	ENSP00000353597.4	Q4U2R8-2
	SLC22A6	ENST00000377871.7	TSL:1	c.1362-1G>C		splice_acceptor intron	N/A	ENSP00000367102.3	Q4U2R8-1
	SLC22A6	ENST00000421062.2	TSL:1	c.1362-133G>C		intron	N/A	ENSP00000404441.2	Q4U2R8-4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000415 AC: 1 AN: 240756 AF XY: 0.00000764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454830 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723866

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111102

Other (OTH) AF: 0.00 AC: 0 AN: 60256

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.8
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.46		Position offset: -9
DS_AL_spliceai		0.76		Position offset: -1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs770486712;

hg19: chr11-62744860;