rs192639023

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_032608.7(MYO18B):c.7147C>T(p.Arg2383Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00451 in 1,613,988 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2383Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0033 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 24 hom. )

Consequence

MYO18B
NM_032608.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.625

Publications

8 publications found

Variant links:

Genes affected

MYO18B (HGNC:18150): (myosin XVIIIB) The protein encoded by this gene may regulate muscle-specific genes when in the nucleus and may influence intracellular trafficking when in the cytoplasm. The encoded protein functions as a homodimer and may interact with F actin. Mutations in this gene are associated with lung cancer. [provided by RefSeq, Jul 2008]

MYO18B Gene-Disease associations (from GenCC):

Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen, G2P

MYO18B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008432716).

BP6

Variant 22-26027121-C-T is Benign according to our data. Variant chr22-26027121-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 377088.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00334 (508/152284) while in subpopulation AMR AF = 0.00562 (86/15308). AF 95% confidence interval is 0.00469. There are 2 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO18B	NM_032608.7 link	c.7147C>T	p.Arg2383Trp	missense_variant	Exon 43 of 44	ENST00000335473.12	NP_115997.5	Q8IUG5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYO18B	ENST00000335473.12 link	c.7147C>T	p.Arg2383Trp	missense_variant	Exon 43 of 44	1	NM_032608.7	ENSP00000334563.8	Q8IUG5-1
MYO18B	ENST00000407587.6 link	c.7150C>T	p.Arg2384Trp	missense_variant	Exon 43 of 44	1		ENSP00000386096.2	Q8IUG5-3
MYO18B	ENST00000536101.5 link	c.7147C>T	p.Arg2383Trp	missense_variant	Exon 43 of 43	1		ENSP00000441229.1	Q8IUG5-1
MYO18B	ENST00000539302.5 link	n.*4605C>T		non_coding_transcript_exon_variant	Exon 41 of 42	1		ENSP00000437587.1	F5H6I8
MYO18B	ENST00000539302.5 link	n.*4605C>T		3_prime_UTR_variant	Exon 41 of 42	1		ENSP00000437587.1	F5H6I8

Frequencies

GnomAD3 genomes

AF:

0.00334

AC:

508

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00563

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00513

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00293

AC:

731

AN:

249190

AF XY:

0.00288

show subpopulations

Gnomad AFR exome

AF:

0.00155

Gnomad AMR exome

AF:

0.00348

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000232

Gnomad NFE exome

AF:

0.00469

Gnomad OTH exome

AF:

0.00512

GnomAD4 exome

AF:

0.00464

AC:

6775

AN:

1461704

Hom.:

Cov.:

AF XY:

0.00443

AC XY:

3219

AN XY:

727138

show subpopulations

African (AFR)

AF:

0.00143

AC:

AN:

33480

American (AMR)

AF:

0.00376

AC:

168

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000497

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000383

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000243

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00563

AC:

6258

AN:

1111864

Other (OTH)

AF:

0.00361

AC:

218

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

477

953

1430

1906

2383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

254

508

762

1016

1270

<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

AF:

0.00334

AC:

508

AN:

152284

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

231

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

41574

American (AMR)

AF:

0.00562

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00513

AC:

349

AN:

68014

Other (OTH)

AF:

0.00710

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00429

Hom.:

Bravo

AF:

0.00361

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00151

AC:

ESP6500EA

AF:

0.00493

AC:

ExAC

AF:

0.00302

AC:

365

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00578

EpiControl

AF:

0.00492

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Sep 08, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYO18B: BP4, BS2 -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MYO18B-related disorder

Benign:1

Nov 16, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.066

T;T;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.83

.;T;T

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.0084

T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.9

L;L;.

PhyloP100

0.63

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Benign

0.14

Sift

Benign

0.17

T;T;T

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

0.29

B;B;.

Vest4

0.27

MVP

0.80

MPC

0.091

ClinPred

0.017

GERP RS

1.2

Varity_R

0.077

gMVP

0.20

Mutation Taster

=97/3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over