XM_011520623.4:c.-1496G>T

Variant names:

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

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.-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
• Publications: 20 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, ClinGen, Orphanet
• multiple endocrine neoplasia

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

  Inheritance: Unknown 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=-0.59).
• BP6: Variant 12-12717002-C-A is Benign according to our data. Variant chr12-12717002-C-A is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000477087.1. 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
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	N/A
	CDKN1B	ENST00000682620.1		n.1631-1823C>A		intron	N/A
	CDKN1B	ENST00000684771.1		n.585-1823C>A		intron	N/A

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

African (AFR) AF: 0.212 AC: 3424 AN: 16142

American (AMR) AF: 0.392 AC: 478 AN: 1218

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 2645 AN: 5922

East Asian (EAS) AF: 0.438 AC: 2726 AN: 6222

South Asian (SAS) AF: 0.443 AC: 7335 AN: 16562

European-Finnish (FIN) AF: 0.500 AC: 142 AN: 284

Middle Eastern (MID) AF: 0.403 AC: 686 AN: 1702

European-Non Finnish (NFE) AF: 0.442 AC: 339605 AN: 768312

Other (OTH) AF: 0.419 AC: 11819 AN: 28180

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

African (AFR) AF: 0.234 AC: 9712 AN: 41528

American (AMR) AF: 0.380 AC: 5811 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1642 AN: 3472

East Asian (EAS) AF: 0.438 AC: 2260 AN: 5160

South Asian (SAS) AF: 0.429 AC: 2071 AN: 4826

European-Finnish (FIN) AF: 0.505 AC: 5352 AN: 10598

Middle Eastern (MID) AF: 0.353 AC: 103 AN: 292

European-Non Finnish (NFE) AF: 0.453 AC: 30747 AN: 67926

Other (OTH) AF: 0.373 AC: 787 AN: 2108

Alfa AF: 0.434 Hom.: 1869

Bravo AF: 0.373

Asia WGS AF: 0.391 AC: 1356 AN: 3472

ClinVar

ClinVar submissions as Germline

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

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.7
DANN	Benign	0.90
PhyloP100		-0.18
PromoterAI		-0.043	Neutral

Splicing

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

Other links and lift over

dbSNP: rs36228499; hg19: chr12-12869936;