rs869312740

Variant names:

• chr22-26026470-G-T
• rs869312740
• NM_032608.7:c.6496G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_032608.7(MYO18B):​c.6496G>T​(p.Glu2166*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYO18B NM_032608.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.30
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 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 22-26026470-G-T is Pathogenic according to our data. Variant chr22-26026470-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 224413.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.6496G>T	p.Glu2166*	stop_gained	Exon 43 of 44	ENST00000335473.12	NP_115997.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO18B	ENST00000335473.12	c.6496G>T	p.Glu2166*	stop_gained	Exon 43 of 44	1	NM_032608.7	ENSP00000334563.8
MYO18B	ENST00000407587.6	c.6499G>T	p.Glu2167*	stop_gained	Exon 43 of 44	1		ENSP00000386096.2
MYO18B	ENST00000536101.5	c.6496G>T	p.Glu2166*	stop_gained	Exon 43 of 43	1		ENSP00000441229.1
MYO18B	ENST00000539302.5	n.*3954G>T		non_coding_transcript_exon_variant	Exon 41 of 42	1		ENSP00000437587.1
MYO18B	ENST00000539302.5	n.*3954G>T		3_prime_UTR_variant	Exon 41 of 42	1		ENSP00000437587.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome Pathogenic:1

Jun 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nemaline myopathy Pathogenic:1

Mar 01, 2024

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1+PS3+PM1+PM2+PP3+PP4+PP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Benign	0.14
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.23	N
PhyloP100		1.3
Vest4		0.11
GERP RS		1.3
Mutation Taster		=9/191	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs869312740; hg19: chr22-26422436;