rs274559

Variant names:

• chr5-132384378-A-G
• rs274559
• NM_003060.4:c.652+77A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003060.4(SLC22A5):​c.652+77A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 1,410,966 control chromosomes in the GnomAD database, including 122,934 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13069 hom., cov: 32)
  • Exomes 𝑓: 0.41 (109865 hom.)
• Consequence: SLC22A5 NM_003060.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.500
• Publications: 34 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-132384378-A-G is Benign according to our data. Variant chr5-132384378-A-G is described in ClinVar as Benign. ClinVar VariationId is 25383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A5	NM_003060.4	c.652+77A>G		intron_variant	Intron 3 of 9	ENST00000245407.8	NP_003051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8	c.652+77A>G		intron_variant	Intron 3 of 9	1	NM_003060.4	ENSP00000245407.3

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61637 AN: 151922 Hom.: 13060 Cov.: 32

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.669

Gnomad SAS AF: 0.640

Gnomad FIN AF: 0.511

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.392

GnomAD4 exome AF: 0.408 AC: 514164 AN: 1258924 Hom.: 109865 AF XY: 0.417 AC XY: 265197 AN XY: 636706

African (AFR) AF: 0.355 AC: 10472 AN: 29462

American (AMR) AF: 0.325 AC: 14423 AN: 44366

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 9980 AN: 24920

East Asian (EAS) AF: 0.668 AC: 25865 AN: 38702

South Asian (SAS) AF: 0.621 AC: 51057 AN: 82210

European-Finnish (FIN) AF: 0.504 AC: 26043 AN: 51672

Middle Eastern (MID) AF: 0.468 AC: 2227 AN: 4754

European-Non Finnish (NFE) AF: 0.379 AC: 351728 AN: 929198

Other (OTH) AF: 0.417 AC: 22369 AN: 53640

GnomAD4 genome AF: 0.406 AC: 61679 AN: 152042 Hom.: 13069 Cov.: 32 AF XY: 0.417 AC XY: 30955 AN XY: 74292

African (AFR) AF: 0.359 AC: 14892 AN: 41494

American (AMR) AF: 0.352 AC: 5381 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1442 AN: 3468

East Asian (EAS) AF: 0.669 AC: 3463 AN: 5174

South Asian (SAS) AF: 0.641 AC: 3090 AN: 4818

European-Finnish (FIN) AF: 0.511 AC: 5391 AN: 10542

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.395 AC: 26837 AN: 67956

Other (OTH) AF: 0.392 AC: 828 AN: 2112

Alfa AF: 0.393 Hom.: 13594

Bravo AF: 0.385

Asia WGS AF: 0.617 AC: 2145 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal carnitine transport defect Benign:3

Jan 23, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 15, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.75
PhyloP100		0.50
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: rs274559; hg19: chr5-131720070; COSMIC: COSV55373571; COSMIC: COSV55373571;