rs36228499

Variant names:

• chr12-12717002-C-A
• rs36228499
• XM_011520623.4:c.-1496G>T

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -16 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Strong

The XM_011520623.4(GPR19):c.-1496G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Note: XM_011520623.4 is not a MANE Select or MANE Plus Clinical transcript for GPR19; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.429 (AC=427,675) in the gnomAD database across 996,668 control chromosomes, including 93,107 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.448. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Variant has been reported in ClinVar as Benign/Likely 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
• Publications: 21 publications found

Genes affected

GPR19 (HGNC:4473): (G protein-coupled receptor 19) Enables G protein-coupled receptor activity. Involved in G protein-coupled receptor signaling pathway. Located in cilium. Is active in plasma membrane. [provided by Alliance of Genome Resources, Jun 2026]

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• multiple endocrine neoplasia

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

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -16 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); No splicing predictor data available.; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4484 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000477087.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CDKN1B ENST00000477087.1	TSL:3	n.154+1119C>A	intron	Intron 2 of 3	Prot:
	CDKN1B ENST00000682620.1		n.1631-1823C>A	intron	Intron 2 of 3	Prot:
	CDKN1B ENST00000684771.1		n.585-1823C>A	intron	Intron 2 of 3	Prot:

CDKN1B ENST00000477087.1

TSL:3

HGVSc / HGVSpn.154+1119C>A

Exon rankIntron 2 of 3

intron

Prot:

CDKN1B ENST00000682620.1

HGVSc / HGVSpn.1631-1823C>A

Exon rankIntron 2 of 3

intron

Prot:

CDKN1B ENST00000684771.1

HGVSc / HGVSpn.585-1823C>A

Exon rankIntron 2 of 3

intron

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.387	AC:58806	Hom:12127	AN:152010	Cov:33
GnomAD4 exome	AF: 0.437	AC:368860	Hom:80979	AN:844544	Cov:31
GnomAD4 genome	AF: 0.387	AC:58815	Hom:12128	AN:152124	Cov:33
TOPMed (Bravo)	AF: 0.373	AC:98765	Hom:19700	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.415	AC:10296	Hom:2281	AN:24820	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.365	AC:855	Hom:155	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.447	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.517	AC:155	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.391	AC:1356	Hom:	AN:3472	Cov:
Korea4K (4,157 Koreans)	AF: 0.451	AC:3236	Hom:	AN:7174	Cov:
Qatari Genome	AF: 0.284	AC:50	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.458	AC:55962	Hom:12797	AN:122148	Cov:
Turkish Variome	AF: 0.456	AC:704	Hom:160	AN:1544	Cov:
UK10K	AF: 0.439	AC:3319	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.436	AC:3911	Hom:851	AN:8960	Cov:

Showing 15 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.140	3351	23966	0.0773	2355	30482

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Multiple endocrine neoplasia type 4 (1)
-	-	1	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	3.4
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.7
DANN	Benign	0.90
GPN-Star LLR	N/A	-1.5
GPN-Star score	N/A	1.5
PhyloP100	Benign	-0.18
PromoterAI	N/A	-0.043	Neutral

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0

Showing 1 of 1 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs36228499;

hg19: chr12-12869936;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar