Genetic Variant MKRN2:c.*318C>T (chr3-12582571-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0740

Variant links:

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]

MKRN2 links:

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 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
MKRN2	NM_014160.5 link	c.*318C>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000170447.12	NP_054879.3
MKRN2	NM_001271707.2 link	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 link	c.*318C>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_014160.5	ENSP00000170447.7		Q9H000-1

Frequencies

GnomAD3 genomes

AF:

0.581

AC:

88349

AN:

151992

Hom.:

26673

Cov.:

show subpopulations

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.:

AF XY:

0.507

AC XY:

23464

AN XY:

46310

show subpopulations

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.:

AF XY:

0.574

AC XY:

42672

AN XY:

74334

show subpopulations

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over