rs15997

chr3-12582571-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014160.5(MKRN2):c.*318C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 242,308 control chromosomes in the GnomAD database, including 39,812 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.58 (26701 hom., cov: 33)
  • Exomes 𝑓: 0.52 (13111 hom.)
• Consequence: MKRN2 NM_014160.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0740

Genes affected

MKRN2 (HGNC:7113): (makorin ring finger protein 2) This gene encodes a probable E3 ubiquitin ligase containing several zinc finger domains, that is a member of the makorin RING zinc-finger protein family. This gene overlaps the v-raf-1 murine leukemia viral oncogene homolog 1 (RAF1) gene in an antisense orientation and may have a co-regulatory function with RAF1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

RAF1 (HGNC:9829): (Raf-1 proto-oncogene, serine/threonine kinase) This gene is the cellular homolog of viral raf gene (v-raf). The encoded protein is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Once activated, the cellular RAF1 protein can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2, which in turn phosphorylate to activate the serine/threonine specific protein kinases, ERK1 and ERK2. Activated ERKs are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration. Mutations in this gene are associated with Noonan syndrome 5 and LEOPARD syndrome 2. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.681 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKRN2	NM_014160.5	c.*318C>T		3_prime_UTR_variant	8/8	ENST00000170447.12
MKRN2	NM_001271707.2	c.*318C>T		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKRN2	ENST00000170447.12	c.*318C>T		3_prime_UTR_variant	8/8	1	NM_014160.5	P1

Frequencies

GnomAD3 genomes AF: 0.581 AC: 88349 AN: 151992 Hom.: 26673 Cov.: 33

Gnomad AFR AF: 0.688

Gnomad AMI AF: 0.712

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.572

Gnomad OTH AF: 0.587

GnomAD4 exome AF: 0.517 AC: 46664 AN: 90198 Hom.: 13111 Cov.: 2 AF XY: 0.507 AC XY: 23464 AN XY: 46310

Gnomad4 AFR exome AF: 0.675

Gnomad4 AMR exome AF: 0.609

Gnomad4 ASJ exome AF: 0.565

Gnomad4 EAS exome AF: 0.114

Gnomad4 SAS exome AF: 0.264

Gnomad4 FIN exome AF: 0.574

Gnomad4 NFE exome AF: 0.568

Gnomad4 OTH exome AF: 0.551

GnomAD4 genome AF: 0.581 AC: 88431 AN: 152110 Hom.: 26701 Cov.: 33 AF XY: 0.574 AC XY: 42672 AN XY: 74334

Gnomad4 AFR AF: 0.688

Gnomad4 AMR AF: 0.598

Gnomad4 ASJ AF: 0.550

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.272

Gnomad4 FIN AF: 0.571

Gnomad4 NFE AF: 0.572

Gnomad4 OTH AF: 0.589

Alfa AF: 0.568 Hom.: 33382

Bravo AF: 0.593

Asia WGS AF: 0.293 AC: 1023 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	1.9
Dann	Benign	0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs15997; hg19: chr3-12624070;