chr22-26026632-AGATTAGAACCT-A

Variant names:

Variant summary

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

The NM_032608.7(MYO18B):c.6660_6670delATTAGAACCTG(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
NM_032608.7 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

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 rank	MANE	Protein	UniProt
MYO18B	NM_032608.7 link	c.6660_6670delATTAGAACCTG	p.Arg2220SerfsTer74	frameshift_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.6660_6670delATTAGAACCTG	p.Arg2220SerfsTer74	frameshift_variant	Exon 43 of 44	1	NM_032608.7	ENSP00000334563.8	Q8IUG5-1
MYO18B	ENST00000407587.6 link	c.6663_6673delATTAGAACCTG	p.Arg2221SerfsTer74	frameshift_variant	Exon 43 of 44	1		ENSP00000386096.2	Q8IUG5-3
MYO18B	ENST00000536101.5 link	c.6660_6670delATTAGAACCTG	p.Arg2220SerfsTer74	frameshift_variant	Exon 43 of 43	1		ENSP00000441229.1	Q8IUG5-1
MYO18B	ENST00000539302.5 link	n.4118_4128delATTAGAACCTG		non_coding_transcript_exon_variant	Exon 41 of 42	1		ENSP00000437587.1	F5H6I8
MYO18B	ENST00000539302.5 link	n.4118_4128delATTAGAACCTG		3_prime_UTR_variant	Exon 41 of 42	1		ENSP00000437587.1	F5H6I8

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome

Pathogenic:5

Dec 18, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYO18B c.6660_6670del11 (p.Arg2220SerfsX74) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.4e-05 in 248956 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MYO18B causing Klippel-Feil Anomaly-Myopathy Dysmorphism Syndrome, allowing no conclusion about variant significance. c.6660_6670del11 has been reported in the literature in individuals affected with Klippel-Feil Anomaly-Myopathy Dysmorphism Syndrome (Scheieffer_2019, Altuame_2021). The following publications have been ascertained in the context of this evaluation (PMID: 31195167, 33179433). ClinVar contains an entry for this variant (Variation ID: 590293). Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 13, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 08, 2021

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Oct 10, 2018

Institute for Genomic Medicine, Nationwide Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

not provided

Pathogenic:2

Jul 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 14, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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