chr12-12717038-G-T

Variant names:

• chr12-12717038-G-T
• rs36228498
• XM_011520623.4:c.-1532C>A

Variant summary

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

The XM_011520623.4(GPR19):​c.-1532C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.818 in 1,004,202 control chromosomes in the GnomAD database, including 338,726 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43856 hom., cov: 35)
  • Exomes 𝑓: 0.83 (294870 hom.)
• Consequence: GPR19 XM_011520623.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.17
• Publications: 2 publications found

Genes affected

GPR19 (HGNC:4473): (G protein-coupled receptor 19) Predicted to enable G protein-coupled receptor activity. Predicted to be involved in G protein-coupled receptor signaling pathway. Located in cilium. [provided by Alliance of Genome Resources, Apr 2022]

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]

CDKN1B Gene-Disease associations (from GenCC):

• multiple endocrine neoplasia type 4

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen
• multiple endocrine neoplasia

  Inheritance: AD Classification: STRONG Submitted by: G2P
• hereditary nonpolyposis colon cancer

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 12-12717038-G-T is Benign according to our data. Variant chr12-12717038-G-T is described in ClinVar as [Benign]. Clinvar id is 1266363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR19	XM_011520623.4	c.-1532C>A		5_prime_UTR_variant	Exon 1 of 4		XP_011518925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1B	ENST00000477087.1	n.154+1155G>T		intron_variant	Intron 2 of 3	3
CDKN1B	ENST00000682620.1	n.1631-1787G>T		intron_variant	Intron 2 of 3
CDKN1B	ENST00000684771.1	n.585-1787G>T		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113667 AN: 152000 Hom.: 43842 Cov.: 35

Gnomad AFR AF: 0.564

Gnomad AMI AF: 0.732

Gnomad AMR AF: 0.680

Gnomad ASJ AF: 0.778

Gnomad EAS AF: 0.944

Gnomad SAS AF: 0.835

Gnomad FIN AF: 0.849

Gnomad MID AF: 0.701

Gnomad NFE AF: 0.837

Gnomad OTH AF: 0.748

GnomAD4 exome AF: 0.830 AC: 707592 AN: 852092 Hom.: 294870 Cov.: 46 AF XY: 0.830 AC XY: 326604 AN XY: 393572

African (AFR) AF: 0.533 AC: 8724 AN: 16376

American (AMR) AF: 0.681 AC: 928 AN: 1362

Ashkenazi Jewish (ASJ) AF: 0.767 AC: 4905 AN: 6394

East Asian (EAS) AF: 0.930 AC: 7258 AN: 7802

South Asian (SAS) AF: 0.837 AC: 13917 AN: 16634

European-Finnish (FIN) AF: 0.851 AC: 245 AN: 288

Middle Eastern (MID) AF: 0.729 AC: 1269 AN: 1740

European-Non Finnish (NFE) AF: 0.837 AC: 646963 AN: 772690

Other (OTH) AF: 0.812 AC: 23383 AN: 28806

GnomAD4 genome AF: 0.748 AC: 113712 AN: 152110 Hom.: 43856 Cov.: 35 AF XY: 0.748 AC XY: 55647 AN XY: 74376

African (AFR) AF: 0.563 AC: 23388 AN: 41506

American (AMR) AF: 0.679 AC: 10387 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.778 AC: 2695 AN: 3466

East Asian (EAS) AF: 0.943 AC: 4869 AN: 5162

South Asian (SAS) AF: 0.837 AC: 4046 AN: 4832

European-Finnish (FIN) AF: 0.849 AC: 9012 AN: 10610

Middle Eastern (MID) AF: 0.699 AC: 204 AN: 292

European-Non Finnish (NFE) AF: 0.837 AC: 56862 AN: 67928

Other (OTH) AF: 0.751 AC: 1584 AN: 2110

Alfa AF: 0.790 Hom.: 6025

Bravo AF: 0.727

Asia WGS AF: 0.848 AC: 2943 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.66
DANN	Benign	0.58
PhyloP100		-2.2
PromoterAI		-0.012	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs36228498; hg19: chr12-12869972;