22-25877989-G-GA

Variant names:

• chr22-25877989-G-GA
• rs970002489
• NM_032608.7:c.4260dupA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_032608.7(MYO18B):​c.4260dupA​(p.Ser1421IlefsTer7) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000035 in 1,429,990 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: MYO18B NM_032608.7 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.37

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-AS1 (HGNC:40831): (MYO18B antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 12 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 22-25877989-G-GA is Pathogenic according to our data. Variant chr22-25877989-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 3701662.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO18B	NM_032608.7	c.4260dupA	p.Ser1421IlefsTer7	frameshift_variant	Exon 25 of 44	ENST00000335473.12	NP_115997.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO18B	ENST00000335473.12	c.4260dupA	p.Ser1421IlefsTer7	frameshift_variant	Exon 25 of 44	1	NM_032608.7	ENSP00000334563.8
MYO18B	ENST00000407587.6	c.4263dupA	p.Ser1422IlefsTer7	frameshift_variant	Exon 25 of 44	1		ENSP00000386096.2
MYO18B	ENST00000536101.5	c.4260dupA	p.Ser1421IlefsTer7	frameshift_variant	Exon 25 of 43	1		ENSP00000441229.1
MYO18B	ENST00000539302.5	n.*1718dupA		non_coding_transcript_exon_variant	Exon 23 of 42	1		ENSP00000437587.1
MYO18B	ENST00000539302.5	n.*1718dupA		3_prime_UTR_variant	Exon 23 of 42	1		ENSP00000437587.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000350 AC: 5 AN: 1429990 Hom.: 0 Cov.: 31 AF XY: 0.00000283 AC XY: 2 AN XY: 707926

Gnomad4 AFR exome AF: 0.0000304

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: 0.00000365

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jun 08, 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.Ser1421Ilefs*7) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYO18B-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs970002489; hg19: chr22-26273956;