chr4-119136572-C-T

Variant names:

• chr4-119136572-C-T
• rs1408647865
• NM_016599.5:c.47C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016599.5(MYOZ2):​c.47C>T​(p.Thr16Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYOZ2 NM_016599.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.75
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24657452).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016599.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOZ2	NM_016599.5	MANE Select	c.47C>T	p.Thr16Ile	missense	Exon 2 of 6	NP_057683.1	Q9NPC6
	MYOZ2	NM_001440645.1		c.47C>T	p.Thr16Ile	missense	Exon 2 of 7	NP_001427574.1
	MYOZ2	NM_001440646.1		c.47C>T	p.Thr16Ile	missense	Exon 2 of 6	NP_001427575.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOZ2	ENST00000307128.6	TSL:1 MANE Select	c.47C>T	p.Thr16Ile	missense	Exon 2 of 6	ENSP00000306997.6	Q9NPC6
	MYOZ2	ENST00000958711.1		c.47C>T	p.Thr16Ile	missense	Exon 2 of 7	ENSP00000628770.1
	MYOZ2	ENST00000890354.1		c.47C>T	p.Thr16Ile	missense	Exon 1 of 5	ENSP00000560413.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250816 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461316 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726964

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.0000224 AC: 1 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111610

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.044
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.97	L
PhyloP100		5.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.12
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.011	D
Polyphen		0.14	B
Vest4		0.41
MutPred		0.53		Loss of helix (P = 0.0068)
MVP		0.81
MPC		0.30
ClinPred		0.50	D
GERP RS		5.7
Varity_R		0.16
gMVP		0.24
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1408647865; hg19: chr4-120057727;