chr2-44319992-A-G

Variant names:

• chr2-44319992-A-G
• rs2289462
• NM_001171613.2:c.*1364T>C

Variant summary

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

The NM_001171613.2(PREPL):​c.*1364T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 566,202 control chromosomes in the GnomAD database, including 122,783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32979 hom., cov: 32)
  • Exomes 𝑓: 0.65 (89804 hom.)
• Consequence: PREPL NM_001171613.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.483
• Publications: 6 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

ENSG00000285542 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-44319992-A-G is Benign according to our data. Variant chr2-44319992-A-G is described in ClinVar as Benign. ClinVar VariationId is 1291996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

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.*1364T>C		3_prime_UTR	Exon 14 of 14	NP_001165084.1	Q4J6C6-4
	SLC3A1	NM_000341.4	MANE Select	c.1618-207A>G		intron	N/A	NP_000332.2	Q07837-1
	PREPL	NM_001171603.1		c.*1364T>C		3_prime_UTR	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.*1364T>C		3_prime_UTR	Exon 14 of 14	ENSP00000387095.2	Q4J6C6-4
	PREPL	ENST00000409936.5	TSL:1	c.*1364T>C		3_prime_UTR	Exon 15 of 15	ENSP00000386543.1	Q4J6C6-1
	SLC3A1	ENST00000260649.11	TSL:1 MANE Select	c.1618-207A>G		intron	N/A	ENSP00000260649.6	Q07837-1

Frequencies

GnomAD3 genomes AF: 0.653 AC: 99306 AN: 151966 Hom.: 32973 Cov.: 32

Gnomad AFR AF: 0.678

Gnomad AMI AF: 0.770

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.695

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.587

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.655

GnomAD4 exome AF: 0.652 AC: 270193 AN: 414118 Hom.: 89804 Cov.: 3 AF XY: 0.655 AC XY: 144854 AN XY: 221070

African (AFR) AF: 0.680 AC: 7985 AN: 11746

American (AMR) AF: 0.583 AC: 10239 AN: 17574

Ashkenazi Jewish (ASJ) AF: 0.696 AC: 8774 AN: 12608

East Asian (EAS) AF: 0.372 AC: 10273 AN: 27584

South Asian (SAS) AF: 0.666 AC: 29001 AN: 43574

European-Finnish (FIN) AF: 0.611 AC: 14598 AN: 23890

Middle Eastern (MID) AF: 0.700 AC: 1247 AN: 1782

European-Non Finnish (NFE) AF: 0.686 AC: 172519 AN: 251334

Other (OTH) AF: 0.648 AC: 15557 AN: 24026

GnomAD4 genome AF: 0.653 AC: 99354 AN: 152084 Hom.: 32979 Cov.: 32 AF XY: 0.644 AC XY: 47847 AN XY: 74332

African (AFR) AF: 0.677 AC: 28089 AN: 41480

American (AMR) AF: 0.605 AC: 9253 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.695 AC: 2413 AN: 3472

East Asian (EAS) AF: 0.315 AC: 1629 AN: 5168

South Asian (SAS) AF: 0.654 AC: 3156 AN: 4824

European-Finnish (FIN) AF: 0.587 AC: 6194 AN: 10558

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.682 AC: 46346 AN: 67984

Other (OTH) AF: 0.651 AC: 1373 AN: 2110

Alfa AF: 0.653 Hom.: 9052

Bravo AF: 0.651

Asia WGS AF: 0.501 AC: 1748 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.6
DANN	Benign	0.75
PhyloP100		0.48
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: rs2289462; hg19: chr2-44547131;