rs192639023

chr22-26027121-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.625

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 377088.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO18B	NM_032608.7	c.7147C>T	p.Arg2383Trp	missense_variant	43/44	ENST00000335473.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO18B	ENST00000335473.12	c.7147C>T	p.Arg2383Trp	missense_variant	43/44	1	NM_032608.7	A2

Frequencies

GnomAD3 genomes AF: 0.00334 AC: 508 AN: 152166 Hom.: 2 Cov.: 32

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

GnomAD3 exomes AF: 0.00293 AC: 731 AN: 249190 Hom.: 2 AF XY: 0.00288 AC XY: 389 AN XY: 135192

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 SAS exome AF: 0.000490

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.: 24 Cov.: 32 AF XY: 0.00443 AC XY: 3219 AN XY: 727138

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.00376

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.00563

Gnomad4 OTH exome AF: 0.00361

GnomAD4 genome AF: 0.00334 AC: 508 AN: 152284 Hom.: 2 Cov.: 32 AF XY: 0.00310 AC XY: 231 AN XY: 74464

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00513

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00448 Hom.: 2

Bravo AF: 0.00361

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00151 AC: 6

ESP6500EA AF: 0.00493 AC: 41

ExAC AF: 0.00302 AC: 365

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00578

EpiControl AF: 0.00492

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 08, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	MYO18B: BP4, BS2 -

MYO18B-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 16, 2020

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	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.066	T;T;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.075	N
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.0084	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Uncertain	0.49	T
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	T
GERP RS		1.2
Varity_R		0.077
gMVP		0.20

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: rs192639023; hg19: chr22-26423087; COSMIC: COSV59135108;