rs199476398

Positions:

• chr4-119150937-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_016599.5(MYOZ2):​c.142T>C​(p.Ser48Pro) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOZ2 NM_016599.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.48

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]

LOC105379404 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 4-119150937-T-C is Pathogenic according to our data. Variant chr4-119150937-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30508.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-119150937-T-C is described in Lovd as [Pathogenic]. Variant chr4-119150937-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOZ2	NM_016599.5	c.142T>C	p.Ser48Pro	missense_variant	3/6	ENST00000307128.6
LOC105379404	XR_001741421.2	n.23A>G		non_coding_transcript_exon_variant	1/2
MYOZ2	XM_006714234.5	c.142T>C	p.Ser48Pro	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOZ2	ENST00000307128.6	c.142T>C	p.Ser48Pro	missense_variant	3/6	1	NM_016599.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy 16 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 23, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2013	- -

not provided Other:1

not provided, no classification provided

curation

Leiden Muscular Dystrophy (MYOZ2)

Apr 20, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.98	D
Vest4		0.91
MutPred		0.95		Loss of phosphorylation at S48 (P = 0.044);
MVP		0.97
MPC		0.69
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.87
gMVP		0.66

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: rs199476398; hg19: chr4-120072092;