Variant rs756408696 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000335473.12(MYO18B):c.6660_6670del(p.Arg2220SerfsTer74) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,613,568 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

MYO18B
ENST00000335473.12 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.40

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 22-26026632-AGATTAGAACCT-A is Pathogenic according to our data. Variant chr22-26026632-AGATTAGAACCT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 590293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO18B	NM_032608.7 linkuse as main transcript	c.6660_6670del	p.Arg2220SerfsTer74	frameshift_variant	43/44	ENST00000335473.12	NP_115997.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO18B	ENST00000335473.12 linkuse as main transcript	c.6660_6670del	p.Arg2220SerfsTer74	frameshift_variant	43/44	1	NM_032608.7	ENSP00000334563	A2	Q8IUG5-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151914

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000442

AC:

AN:

248956

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135148

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000975

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000154

AC:

225

AN:

1461654

Hom.:

AF XY:

0.000161

AC XY:

117

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000197

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151914

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74178

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 13, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 27, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine, Nationwide Children's Hospital	Oct 10, 2018	This individual is compound heterozygous for two likely pathogenic changes in the MYO18B gene. These frameshift alterations encode a premature stop of translation (ACMG: PVS1). The first, p.Arg2220SerfsTer74, occurs at an amino acid position 86% of the way through the full length protein, and the second, p.Leu2257SerfsTer16, occurs 88% of the way through the full length protein. These alterations occur within exon 43 of the transcript, NM_032608.5, within the penultimate exon of the gene (also representing the final coding exon of the transcript). These variants are very rare (p.Arg2220SerfsTer74) or absent (p.Leu2257SerfsTer16) from population databases (gnomAD) (ACMG: PM2). MYO18B is associated with autosomal recessive Klippel-Feil syndrome-4 with nemaline myopathy and facial dysmorphism (OMIM: 616549). Limited phenotypic data have been described in the literature and medical databases, however MYO18B variants encoding a premature stop of translation have been previously documented in association with myopathy, mild short stature, microcephaly, cardiomyopathy, pectus deformity, digit anomalies and distinctive facies (PMID: 25748484; 27858739). Characterization of the effect of a premature stop of translation within MYO18B has been described in the setting of in-vitro analyses. Examination of an affected patient's lymphocytes harboring a nonsense alteration (p.Ser2303Ter) demonstrated markedly diminished MYO18B transcript by quantitative PCR in comparison to a control, therefore hypothesized to be consistent with nonsense-mediated decay (PMID: 25748484). Moreover, western blot analysis and immunostaining of skeletal muscle in another patient harboring a nonsense alteration (p.Glu2166Ter) demonstrated the absence of the C-terminus of the protein hypothesized to be consistent with protein truncation (PMID: 27858739). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Sep 08, 2021	This sequence variant is an 11 base pair deletion in exon 43 of the Myosin 18B protein and results in an early termition codon 74 amino acids downstream of the frameshift at Arg2220. This variant is predicted to generate a non-functiol allele through either the expression of a truncated protein or a loss of MYO18 expression due to nonsense mediated decay. This is a previously reported variant (ClinVar) that is rare in control population datasets (gnomAD database, 11/248956 alleles or 0.004%). This variant has been observed in an individual with MYO18B-related disease and was a compound heterozygote for a second truncating variant in MYO18 (PMID: 31195167). Given the evidence we consider this variant to be likely pathogenic. ACMG Criteria: PM2, PVS1 -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 01, 2023	This sequence change creates a premature translational stop signal (p.Arg2220Serfs*74) in the MYO18B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO18B are known to be pathogenic (PMID: 25748484, 32184166, 32637634). This variant is present in population databases (rs756408696, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Klippel-Feil syndrome (PMID: 31195167, 33179433). ClinVar contains an entry for this variant (Variation ID: 590293). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2024	Frameshift variant predicted to result in abnormal protein length as the last 348 amino acids are replaced with 73 different amino acids, and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 32278351, 32184166, 33179433, 31195167) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over