4-119150976-C-A

Variant names:

• chr4-119150976-C-A
• rs755233280
• NM_016599.5:c.181C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016599.5(MYOZ2):​c.181C>A​(p.Arg61Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R61H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOZ2 NM_016599.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.59
• Publications: 0 publications found

Genes affected

MYOZ2 (HGNC:1330): (myozenin 2) The protein encoded by this gene belongs to a family of sarcomeric proteins that bind to calcineurin, a phosphatase involved in calcium-dependent signal transduction in diverse cell types. These family members tether calcineurin to alpha-actinin at the z-line of the sarcomere of cardiac and skeletal muscle cells, and thus they are important for calcineurin signaling. Mutations in this gene cause cardiomyopathy familial hypertrophic type 16, a hereditary heart disorder. [provided by RefSeq, Aug 2011]

MYOZ2 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy 16

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

LOC105379404 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOZ2	NM_016599.5	c.181C>A	p.Arg61Ser	missense_variant	Exon 3 of 6	ENST00000307128.6	NP_057683.1
MYOZ2	NM_001440645.1	c.181C>A	p.Arg61Ser	missense_variant	Exon 3 of 7		NP_001427574.1
MYOZ2	NM_001440646.1	c.181C>A	p.Arg61Ser	missense_variant	Exon 3 of 6		NP_001427575.1
LOC105379404	XR_001741421.2	n.-17G>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOZ2	ENST00000307128.6	c.181C>A	p.Arg61Ser	missense_variant	Exon 3 of 6	1	NM_016599.5	ENSP00000306997.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		5.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.90		Gain of phosphorylation at R61 (P = 0.0176);
MVP		0.98
MPC		0.75
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.93
gMVP		0.74
Mutation Taster		=10/90	disease causing

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

Other links and lift over

dbSNP: rs755233280; hg19: chr4-120072131;