rs2073642

Variant names:

• chr5-132378082-C-T
• rs2073642
• NM_003060.4:c.394-296C>T

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.394-296C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0787 in 1,538,810 control chromosomes in the GnomAD database, including 6,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (612 hom., cov: 32)
  • Exomes 𝑓: 0.079 (5421 hom.)
• Consequence: SLC22A5 NM_003060.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00400
• Publications: 8 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=-0.85).
• BP6: Variant 5-132378082-C-T is Benign according to our data. Variant chr5-132378082-C-T is described in ClinVar as Benign. ClinVar VariationId is 671627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A5	NM_003060.4	c.394-296C>T		intron_variant	Intron 1 of 9	ENST00000245407.8	NP_003051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8	c.394-296C>T		intron_variant	Intron 1 of 9	1	NM_003060.4	ENSP00000245407.3

Frequencies

GnomAD3 genomes AF: 0.0801 AC: 12186 AN: 152110 Hom.: 615 Cov.: 32

Gnomad AFR AF: 0.0724

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.0511

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.0731

Gnomad FIN AF: 0.0769

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0755

Gnomad OTH AF: 0.0794

GnomAD4 exome AF: 0.0786 AC: 108943 AN: 1386582 Hom.: 5421 Cov.: 31 AF XY: 0.0781 AC XY: 53396 AN XY: 683348

African (AFR) AF: 0.0698 AC: 2174 AN: 31160

American (AMR) AF: 0.0380 AC: 1306 AN: 34412

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2734 AN: 24274

East Asian (EAS) AF: 0.301 AC: 10749 AN: 35664

South Asian (SAS) AF: 0.0593 AC: 4578 AN: 77216

European-Finnish (FIN) AF: 0.0764 AC: 3656 AN: 47824

Middle Eastern (MID) AF: 0.0660 AC: 340 AN: 5148

European-Non Finnish (NFE) AF: 0.0732 AC: 78620 AN: 1073428

Other (OTH) AF: 0.0833 AC: 4786 AN: 57456

GnomAD4 genome AF: 0.0801 AC: 12190 AN: 152228 Hom.: 612 Cov.: 32 AF XY: 0.0795 AC XY: 5919 AN XY: 74430

African (AFR) AF: 0.0725 AC: 3011 AN: 41536

American (AMR) AF: 0.0510 AC: 780 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 391 AN: 3472

East Asian (EAS) AF: 0.275 AC: 1422 AN: 5162

South Asian (SAS) AF: 0.0729 AC: 352 AN: 4826

European-Finnish (FIN) AF: 0.0769 AC: 815 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0755 AC: 5133 AN: 68016

Other (OTH) AF: 0.0795 AC: 168 AN: 2112

Alfa AF: 0.0749 Hom.: 749

Bravo AF: 0.0782

Asia WGS AF: 0.134 AC: 466 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal carnitine transport defect Benign:2

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

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.7
DANN	Benign	0.46
PhyloP100		-0.0040
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: rs2073642; hg19: chr5-131713774; COSMIC: COSV55375161;