rs149012504

chr2-44321418-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/18 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:2
• Conservation: PhyloP100: 2.57

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREPL	NM_001171613.2	c.1855G>A	p.Glu619Lys	missense_variant	14/14	ENST00000409411.6
SLC3A1	NM_000341.4	c.*779C>T		3_prime_UTR_variant	10/10	ENST00000260649.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREPL	ENST00000409411.6	c.1855G>A	p.Glu619Lys	missense_variant	14/14	1	NM_001171613.2	P4
SLC3A1	ENST00000260649.11	c.*779C>T		3_prime_UTR_variant	10/10	1	NM_000341.4	P1

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

GnomAD3 exomes AF: 0.00141 AC: 354 AN: 250808 Hom.: 4 AF XY: 0.00102 AC XY: 138 AN XY: 135592

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 SAS exome AF: 0.0000654

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

Gnomad4 AFR exome AF: 0.0176

Gnomad4 AMR exome AF: 0.000940

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00127

Gnomad4 NFE exome AF: 0.0000513

Gnomad4 OTH exome AF: 0.00176

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

Gnomad4 AFR AF: 0.0176

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00103 Hom.: 3

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

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myasthenic syndrome, congenital, 22 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 11, 2015

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.86	D;.;.;.;.;.;D;D;D
MetaRNN	Benign	0.0053	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.64	N;N;N;N;N;N;N;N;N;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.15	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.074
Sift	Benign	0.67	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.89	T;T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.0020, 0.20	.;.;.;B;B;B;B;B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs149012504; hg19: chr2-44548557;