rs36228499

chr12-12717002-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The XM_011520623.4(GPR19):c.-1496G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 996,668 control chromosomes in the GnomAD database, including 93,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12128 hom., cov: 33)
  • Exomes 𝑓: 0.44 (80979 hom.)
• Consequence: GPR19 XM_011520623.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.177

Genes affected

GPR19 (HGNC:):

CDKN1B (HGNC:1785): (cyclin dependent kinase inhibitor 1B) This gene encodes a cyclin-dependent kinase inhibitor, which shares a limited similarity with CDK inhibitor CDKN1A/p21. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. The degradation of this protein, which is triggered by its CDK dependent phosphorylation and subsequent ubiquitination by SCF complexes, is required for the cellular transition from quiescence to the proliferative state. Mutations in this gene are associated with multiple endocrine neoplasia type IV (MEN4). [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 12-12717002-C-A is Benign according to our data. Variant chr12-12717002-C-A is described in ClinVar as [Benign]. Clinvar id is 695291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR19	XM_011520623.4	c.-1496G>T		5_prime_UTR_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1B	ENST00000477087.1	n.154+1119C>A		intron_variant, non_coding_transcript_variant		3
CDKN1B	ENST00000682620.1	n.1631-1823C>A		intron_variant, non_coding_transcript_variant
CDKN1B	ENST00000684771.1	n.585-1823C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58806 AN: 152010 Hom.: 12127 Cov.: 33

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.363

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.375

GnomAD4 exome AF: 0.437 AC: 368860 AN: 844544 Hom.: 80979 Cov.: 31 AF XY: 0.436 AC XY: 170019 AN XY: 390116

Gnomad4 AFR exome AF: 0.212

Gnomad4 AMR exome AF: 0.392

Gnomad4 ASJ exome AF: 0.447

Gnomad4 EAS exome AF: 0.438

Gnomad4 SAS exome AF: 0.443

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.442

Gnomad4 OTH exome AF: 0.419

GnomAD4 genome AF: 0.387 AC: 58815 AN: 152124 Hom.: 12128 Cov.: 33 AF XY: 0.390 AC XY: 28992 AN XY: 74386

Gnomad4 AFR AF: 0.234

Gnomad4 AMR AF: 0.380

Gnomad4 ASJ AF: 0.473

Gnomad4 EAS AF: 0.438

Gnomad4 SAS AF: 0.429

Gnomad4 FIN AF: 0.505

Gnomad4 NFE AF: 0.453

Gnomad4 OTH AF: 0.373

Alfa AF: 0.434 Hom.: 1869

Bravo AF: 0.373

Asia WGS AF: 0.391 AC: 1356 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2020

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2019

This variant is associated with the following publications: (PMID: 15061869, 19667240) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	8.7
Dann	Benign	0.90

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs36228499; hg19: chr12-12869936;