2-44321418-C-T

Variant names:

• chr2-44321418-C-T
• rs149012504
• NM_001171613.2:c.1855G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001171613.2(PREPL):​c.1855G>A​(p.Glu619Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,612,692 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (10 hom.)
• Consequence: PREPL NM_001171613.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.57
• Publications: 4 publications found

Genes affected

PREPL (HGNC:30228): (prolyl endopeptidase like) The protein encoded by this gene belongs to the prolyl oligopeptidase subfamily of serine peptidases. Mutations in this gene have been associated with hypotonia-cystinuria syndrome, also known as the 2p21 deletion syndrome. Several alternatively spliced transcript variants encoding either the same or different isoforms have been described for this gene.[provided by RefSeq, Jan 2010]

SLC3A1 (HGNC:11025): (solute carrier family 3 member 1) This gene encodes a type II membrane glycoprotein which is one of the components of the renal amino acid transporter which transports neutral and basic amino acids in the renal tubule and intestinal tract. Mutations and deletions in this gene are associated with cystinuria. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

SLC3A1 Gene-Disease associations (from GenCC):

• cystinuria

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, PanelApp Australia
• cystinuria type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005270511).
• BP6: Variant 2-44321418-C-T is Benign according to our data. Variant chr2-44321418-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00518 (787/152024) while in subpopulation AFR AF = 0.0176 (729/41456). AF 95% confidence interval is 0.0165. There are 9 homozygotes in GnomAd4. There are 371 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001171613.2. 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
	PREPL	NM_001171613.2	MANE Select	c.1855G>A	p.Glu619Lys	missense	Exon 14 of 14	NP_001165084.1	Q4J6C6-4
	SLC3A1	NM_000341.4	MANE Select	c.*779C>T		3_prime_UTR	Exon 10 of 10	NP_000332.2	Q07837-1
	PREPL	NM_001171603.1		c.2122G>A	p.Glu708Lys	missense	Exon 15 of 15	NP_001165074.1	Q4J6C6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PREPL	ENST00000409411.6	TSL:1 MANE Select	c.1855G>A	p.Glu619Lys	missense	Exon 14 of 14	ENSP00000387095.2	Q4J6C6-4
	PREPL	ENST00000260648.10	TSL:1	c.2122G>A	p.Glu708Lys	missense	Exon 14 of 14	ENSP00000260648.6	Q4J6C6-1
	PREPL	ENST00000409936.5	TSL:1	c.2122G>A	p.Glu708Lys	missense	Exon 15 of 15	ENSP00000386543.1	Q4J6C6-1

Frequencies

GnomAD3 genomes AF: 0.00516 AC: 784 AN: 151908 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00141 AC: 354 AN: 250808 AF XY: 0.00102

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.0000882

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000603 AC: 881 AN: 1460668 Hom.: 10 Cov.: 30 AF XY: 0.000524 AC XY: 381 AN XY: 726680

African (AFR) AF: 0.0176 AC: 587 AN: 33432

American (AMR) AF: 0.000940 AC: 42 AN: 44668

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39672

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86170

European-Finnish (FIN) AF: 0.00127 AC: 68 AN: 53392

Middle Eastern (MID) AF: 0.00261 AC: 15 AN: 5758

European-Non Finnish (NFE) AF: 0.0000513 AC: 57 AN: 1111130

Other (OTH) AF: 0.00176 AC: 106 AN: 60342

GnomAD4 genome AF: 0.00518 AC: 787 AN: 152024 Hom.: 9 Cov.: 32 AF XY: 0.00499 AC XY: 371 AN XY: 74298

African (AFR) AF: 0.0176 AC: 729 AN: 41456

American (AMR) AF: 0.00177 AC: 27 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67978

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

Alfa AF: 0.00207 Hom.: 7

Bravo AF: 0.00612

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00177 AC: 215

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.0000546

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Myasthenic syndrome, congenital, 22 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.93	N
PhyloP100		2.6
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.074
Sift	Benign	0.67	T
Sift4G	Benign	0.89	T
Polyphen		0.0010	B
Vest4		0.28
MVP		0.19
MPC		0.0048
ClinPred		0.012	T
GERP RS		4.2
Varity_R		0.057
gMVP		0.34
Mutation Taster		=99/1	polymorphism

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: rs149012504; hg19: chr2-44548557;