rs756408696

chr22-26026632-AGATTAGAACCT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_032608.7(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 NM_032608.7 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.40

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 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	UniProt
MYO18B	NM_032608.7	c.6660_6670del	p.Arg2220SerfsTer74	frameshift_variant	43/44	ENST00000335473.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO18B	ENST00000335473.12	c.6660_6670del	p.Arg2220SerfsTer74	frameshift_variant	43/44	1	NM_032608.7	A2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151914 Hom.: 0 Cov.: 32

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: 11 AN: 248956 Hom.: 0 AF XY: 0.0000444 AC XY: 6 AN XY: 135148

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.: 0 AF XY: 0.000161 AC XY: 117 AN XY: 727118

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: 3 AN: 151914 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74178

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome Pathogenic:3

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	Revvity Omics, Revvity	Aug 13, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs756408696; hg19: chr22-26422598;