NM_016599.5:c.561-14_561-13dupTT

Variant names:

• chr4-119185943-G-GTT
• rs112369914
• NM_016599.5:c.561-14_561-13dupTT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_016599.5(MYOZ2):​c.561-14_561-13dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,441,644 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (5 hom., cov: 18)
  • Exomes 𝑓: 0.0020 (1 hom.)
• Consequence: MYOZ2 NM_016599.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• 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 -6 ACMG points.

• BP6: Variant 4-119185943-G-GTT is Benign according to our data. Variant chr4-119185943-G-GTT is described in ClinVar as Likely_benign. ClinVar VariationId is 178659.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 701 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.561-14_561-13dupTT		intron	N/A	NP_057683.1
	MYOZ2	NM_001440645.1		c.607-14_607-13dupTT		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.561-23_561-22insTT		intron	N/A	ENSP00000306997.6
	MYOZ2	ENST00000958711.1		c.654-23_654-22insTT		intron	N/A	ENSP00000628770.1
	MYOZ2	ENST00000890354.1		c.561-23_561-22insTT		intron	N/A	ENSP00000560413.1

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 694 AN: 149250 Hom.: 5 Cov.: 18

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00207

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000501

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000343

Gnomad OTH AF: 0.00388

GnomAD2 exomes AF: 0.00268 AC: 484 AN: 180466 AF XY: 0.00210

Gnomad AFR exome AF: 0.0193

Gnomad AMR exome AF: 0.00290

Gnomad ASJ exome AF: 0.00107

Gnomad EAS exome AF: 0.000304

Gnomad FIN exome AF: 0.00170

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00195 AC: 2525 AN: 1292294 Hom.: 1 Cov.: 26 AF XY: 0.00185 AC XY: 1198 AN XY: 646162

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

African (AFR) AF: 0.0216 AC: 611 AN: 28226

American (AMR) AF: 0.00265 AC: 108 AN: 40688

Ashkenazi Jewish (ASJ) AF: 0.00106 AC: 25 AN: 23616

East Asian (EAS) AF: 0.000469 AC: 17 AN: 36282

South Asian (SAS) AF: 0.00168 AC: 129 AN: 76914

European-Finnish (FIN) AF: 0.00150 AC: 71 AN: 47212

Middle Eastern (MID) AF: 0.00190 AC: 10 AN: 5270

European-Non Finnish (NFE) AF: 0.00143 AC: 1404 AN: 980568

Other (OTH) AF: 0.00280 AC: 150 AN: 53518

⚠️ 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: 0.00469 AC: 701 AN: 149350 Hom.: 5 Cov.: 18 AF XY: 0.00454 AC XY: 330 AN XY: 72760

African (AFR) AF: 0.0155 AC: 634 AN: 40818

American (AMR) AF: 0.00207 AC: 31 AN: 15000

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.00 AC: 0 AN: 4712

European-Finnish (FIN) AF: 0.000501 AC: 5 AN: 9980

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

European-Non Finnish (NFE) AF: 0.000343 AC: 23 AN: 67028

Other (OTH) AF: 0.00385 AC: 8 AN: 2080

Alfa AF: 0.00254 Hom.: 221

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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

Splicing

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

Other links and lift over

dbSNP: rs112369914; hg19: chr4-120107098;