rs15997

Variant names:

• chr3-12582571-C-T
• rs15997
• NM_014160.5:c.*318C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 22 publications found

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]

RAF1 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Noonan syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, G2P
• dilated cardiomyopathy 1NN

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• LEOPARD syndrome 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
MKRN2	NM_014160.5	c.*318C>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000170447.12	NP_054879.3
MKRN2	NM_001271707.2	c.*318C>T		3_prime_UTR_variant	Exon 7 of 7		NP_001258636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKRN2	ENST00000170447.12	c.*318C>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_014160.5	ENSP00000170447.7

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

African (AFR) AF: 0.675 AC: 2710 AN: 4012

American (AMR) AF: 0.609 AC: 3225 AN: 5292

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1745 AN: 3090

East Asian (EAS) AF: 0.114 AC: 836 AN: 7350

South Asian (SAS) AF: 0.264 AC: 1517 AN: 5742

European-Finnish (FIN) AF: 0.574 AC: 2176 AN: 3788

Middle Eastern (MID) AF: 0.473 AC: 178 AN: 376

European-Non Finnish (NFE) AF: 0.568 AC: 31276 AN: 55100

Other (OTH) AF: 0.551 AC: 3001 AN: 5448

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

African (AFR) AF: 0.688 AC: 28532 AN: 41484

American (AMR) AF: 0.598 AC: 9134 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 1908 AN: 3468

East Asian (EAS) AF: 0.109 AC: 563 AN: 5186

South Asian (SAS) AF: 0.272 AC: 1308 AN: 4816

European-Finnish (FIN) AF: 0.571 AC: 6031 AN: 10560

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.572 AC: 38919 AN: 67988

Other (OTH) AF: 0.589 AC: 1247 AN: 2116

Alfa AF: 0.582 Hom.: 50736

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
PhyloP100		0.074
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs15997; hg19: chr3-12624070;