chr5-132378414-C-T

Variant names:

• chr5-132378414-C-T
• rs10040427
• NM_003060.4:c.430C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 4P and 20B. PM1 PM5 BP4_Strong BP6_Very_Strong BA1

The NM_001308122.2(SLC22A5):​c.502C>T​(p.Leu168Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,614,242 control chromosomes in the GnomAD database, including 231 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L168P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.022 (103 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (128 hom.)
• Consequence: SLC22A5 NM_001308122.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.325
• Publications: 19 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 -16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_001308122.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-132378415-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3591687.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0027811527).
• BP6: Variant 5-132378414-C-T is Benign according to our data. Variant chr5-132378414-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 25373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0739 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308122.2. 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.430C>T	p.Leu144Phe	missense	Exon 2 of 10	NP_003051.1
	SLC22A5	NM_001308122.2		c.502C>T	p.Leu168Phe	missense	Exon 3 of 11	NP_001295051.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A5	ENST00000245407.8	TSL:1 MANE Select	c.430C>T	p.Leu144Phe	missense	Exon 2 of 10	ENSP00000245407.3
	SLC22A5	ENST00000435065.7	TSL:1	c.502C>T	p.Leu168Phe	missense	Exon 3 of 11	ENSP00000402760.2
	SLC22A5	ENST00000448810.6	TSL:1	n.430C>T		non_coding_transcript_exon	Exon 2 of 10	ENSP00000401860.2

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3290 AN: 152250 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.0761

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00579 AC: 1456 AN: 251494 AF XY: 0.00413

Gnomad AFR exome AF: 0.0788

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00222 AC: 3252 AN: 1461874 Hom.: 128 Cov.: 31 AF XY: 0.00192 AC XY: 1393 AN XY: 727240

African (AFR) AF: 0.0767 AC: 2568 AN: 33472

American (AMR) AF: 0.00405 AC: 181 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000185 AC: 16 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53418

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.000146 AC: 162 AN: 1112006

Other (OTH) AF: 0.00487 AC: 294 AN: 60392

GnomAD4 genome AF: 0.0216 AC: 3297 AN: 152368 Hom.: 103 Cov.: 32 AF XY: 0.0206 AC XY: 1538 AN XY: 74512

African (AFR) AF: 0.0761 AC: 3162 AN: 41570

American (AMR) AF: 0.00568 AC: 87 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68042

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.00544 Hom.: 87

Bravo AF: 0.0246

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0822 AC: 362

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00738 AC: 896

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	Renal carnitine transport defect (7)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.016	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.33
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.084
Sift	Benign	0.26	T
Sift4G	Benign	0.30	T
Polyphen		0.10	B
Vest4		0.18
MVP		0.84
MPC		0.33
ClinPred		0.0073	T
GERP RS		3.0
Varity_R		0.10
gMVP		0.72
Mutation Taster		=84/16	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: rs10040427; hg19: chr5-131714106;