chr4-119185943-GT-G

Variant names:

• chr4-119185943-GT-G
• rs112369914
• NM_016599.5:c.561-13delT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_016599.5(MYOZ2):​c.561-13delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000815 in 1,440,188 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., cov: 18)
  • Exomes 𝑓: 0.00090 (1 hom.)
• Consequence: MYOZ2 NM_016599.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.359
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 15 AD gene.

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.561-13delT		intron	N/A	NP_057683.1
	MYOZ2	NM_001440645.1		c.607-13delT		intron	N/A	NP_001427574.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOZ2	ENST00000307128.6	TSL:1 MANE Select	c.561-22delT		intron	N/A	ENSP00000306997.6
	MYOZ2	ENST00000958711.1		c.654-22delT		intron	N/A	ENSP00000628770.1
	MYOZ2	ENST00000890354.1		c.561-22delT		intron	N/A	ENSP00000560413.1

Frequencies

GnomAD3 genomes AF: 0.000101 AC: 15 AN: 149248 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.000123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.000424

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000895

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00131 AC: 237 AN: 180466 AF XY: 0.00135

Gnomad AFR exome AF: 0.000324

Gnomad AMR exome AF: 0.000644

Gnomad ASJ exome AF: 0.000268

Gnomad EAS exome AF: 0.00122

Gnomad FIN exome AF: 0.00198

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.00136

GnomAD4 exome AF: 0.000898 AC: 1159 AN: 1290840 Hom.: 1 Cov.: 26 AF XY: 0.000779 AC XY: 503 AN XY: 645840

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000554 AC: 16 AN: 28904

American (AMR) AF: 0.000541 AC: 22 AN: 40650

Ashkenazi Jewish (ASJ) AF: 0.000254 AC: 6 AN: 23640

East Asian (EAS) AF: 0.000165 AC: 6 AN: 36298

South Asian (SAS) AF: 0.000878 AC: 68 AN: 77436

European-Finnish (FIN) AF: 0.000826 AC: 39 AN: 47242

Middle Eastern (MID) AF: 0.000944 AC: 5 AN: 5296

European-Non Finnish (NFE) AF: 0.000978 AC: 956 AN: 977860

Other (OTH) AF: 0.000766 AC: 41 AN: 53514

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000100 AC: 15 AN: 149348 Hom.: 0 Cov.: 18 AF XY: 0.0000825 AC XY: 6 AN XY: 72754

African (AFR) AF: 0.000122 AC: 5 AN: 40824

American (AMR) AF: 0.00 AC: 0 AN: 14998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.000391 AC: 2 AN: 5110

South Asian (SAS) AF: 0.000425 AC: 2 AN: 4710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000895 AC: 6 AN: 67024

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00418 Hom.: 221

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism

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: rs112369914; hg19: chr4-120107098;