Genetic Variant NMRK2:p.Arg194His (chr19-3942161-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_170678.3(NMRK2):c.581G>A(p.Arg194His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

NMRK2
NM_170678.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.410

Publications

1 publications found

Variant links:

Genes affected

NMRK2 (HGNC:17871): (nicotinamide riboside kinase 2) Enables ribosylnicotinamide kinase activity and ribosylnicotinate kinase activity. Predicted to be involved in NAD metabolic process. Predicted to act upstream of or within negative regulation of myoblast differentiation. Located in nucleoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

NMRK2 links:

ENSG00000289254 (HGNC:):

ENSG00000289254 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056898475).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170678.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NMRK2	NM_170678.3	MANE Select	c.581G>A	p.Arg194His	missense	Exon 8 of 8	NP_733778.1	Q9NPI5-1
NMRK2	NM_001289117.2		c.596G>A	p.Arg199His	missense	Exon 8 of 8	NP_001276046.1	Q9NPI5-3
NMRK2	NM_001375467.2		c.509G>A	p.Arg170His	missense	Exon 6 of 6	NP_001362396.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NMRK2	ENST00000168977.7	TSL:2 MANE Select	c.581G>A	p.Arg194His	missense	Exon 8 of 8	ENSP00000168977.1	Q9NPI5-1
NMRK2	ENST00000593949.1	TSL:1	c.596G>A	p.Arg199His	missense	Exon 7 of 7	ENSP00000472581.1	Q9NPI5-3
NMRK2	ENST00000968742.1		c.638G>A	p.Arg213His	missense	Exon 7 of 7	ENSP00000638801.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250082

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460960

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726798

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111954

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.066

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.021

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.41

M_CAP

Benign

0.011

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

PhyloP100

0.41

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.020

REVEL

Benign

0.013

Sift

Benign

0.31

Sift4G

Benign

0.13

Polyphen

0.0030

Vest4

0.055

MutPred

0.26

Gain of glycosylation at S198 (P = 0.0757)

MVP

0.30

MPC

0.14

ClinPred

0.042

GERP RS

-3.2

Varity_R

0.020

gMVP

0.20

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over