rs4646301

Variant names:

• chr5-132375408-G-A
• rs4646301
• NM_003060.4:c.394-2970G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003060.4(SLC22A5):​c.394-2970G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0768 in 152,270 control chromosomes in the GnomAD database, including 579 homozygotes. 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: 𝑓 0.077 (579 hom., cov: 32)
• Consequence: SLC22A5 NM_003060.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0410
• Publications: 7 publications found

Genes affected

SLC22A5 (HGNC:10969): (solute carrier family 22 member 5) Polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins. The encoded protein is a plasma integral membrane protein which functions both as an organic cation transporter and as a sodium-dependent high affinity carnitine transporter. The encoded protein is involved in the active cellular uptake of carnitine. Mutations in this gene are the cause of systemic primary carnitine deficiency (CDSP), an autosomal recessive disorder manifested early in life by hypoketotic hypoglycemia and acute metabolic decompensation, and later in life by skeletal myopathy or cardiomyopathy. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2015]

SLC22A5 Gene-Disease associations (from GenCC):

• systemic primary carnitine deficiency disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• short QT syndrome

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003060.4. 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
	SLC22A5	NM_003060.4	MANE Select	c.394-2970G>A		intron	N/A	NP_003051.1
	SLC22A5	NM_001308122.2		c.394-2756G>A		intron	N/A	NP_001295051.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A5	ENST00000245407.8	TSL:1 MANE Select	c.394-2970G>A		intron	N/A	ENSP00000245407.3
	SLC22A5	ENST00000435065.7	TSL:1	c.394-2756G>A		intron	N/A	ENSP00000402760.2
	SLC22A5	ENST00000448810.6	TSL:1	n.394-2970G>A		intron	N/A	ENSP00000401860.2

Frequencies

GnomAD3 genomes AF: 0.0768 AC: 11688 AN: 152152 Hom.: 582 Cov.: 32

Gnomad AFR AF: 0.0610

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.0497

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.0731

Gnomad FIN AF: 0.0769

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0754

Gnomad OTH AF: 0.0770

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0768 AC: 11691 AN: 152270 Hom.: 579 Cov.: 32 AF XY: 0.0763 AC XY: 5684 AN XY: 74456

African (AFR) AF: 0.0611 AC: 2538 AN: 41550

American (AMR) AF: 0.0497 AC: 760 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 390 AN: 3468

East Asian (EAS) AF: 0.275 AC: 1423 AN: 5170

South Asian (SAS) AF: 0.0729 AC: 352 AN: 4828

European-Finnish (FIN) AF: 0.0769 AC: 816 AN: 10612

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0754 AC: 5131 AN: 68020

Other (OTH) AF: 0.0771 AC: 163 AN: 2114

Alfa AF: 0.0744 Hom.: 721

Bravo AF: 0.0741

Asia WGS AF: 0.133 AC: 462 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.2
DANN	Benign	0.34
PhyloP100		-0.041
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs4646301; hg19: chr5-131711100;