chr4-119136516-C-CA

Variant names:

• chr4-119136516-C-CA
• rs397517288
• NM_016599.5:c.-3dupA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_016599.5(MYOZ2):​c.-3dupA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,612,438 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (6 hom.)
• Consequence: MYOZ2 NM_016599.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.31
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 4-119136516-C-CA is Benign according to our data. Variant chr4-119136516-C-CA is described in ClinVar as Benign. ClinVar VariationId is 45778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00534 (812/152014) while in subpopulation AFR AF = 0.0169 (699/41464). AF 95% confidence interval is 0.0158. There are 6 homozygotes in GnomAd4. There are 385 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 812 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.-3dupA		5_prime_UTR	Exon 2 of 6	NP_057683.1	Q9NPC6
	MYOZ2	NM_001440645.1		c.-3dupA		5_prime_UTR	Exon 2 of 7	NP_001427574.1
	MYOZ2	NM_001440646.1		c.-3dupA		5_prime_UTR	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.-3dupA		5_prime_UTR	Exon 2 of 6	ENSP00000306997.6	Q9NPC6
	MYOZ2	ENST00000958711.1		c.-3dupA		5_prime_UTR	Exon 2 of 7	ENSP00000628770.1
	MYOZ2	ENST00000890354.1		c.-3dupA		5_prime_UTR	Exon 1 of 5	ENSP00000560413.1

Frequencies

GnomAD3 genomes AF: 0.00530 AC: 805 AN: 151896 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0168

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00629

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00116 AC: 290 AN: 249782 AF XY: 0.000859

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.000900

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.000559 AC: 817 AN: 1460424 Hom.: 6 Cov.: 31 AF XY: 0.000471 AC XY: 342 AN XY: 726522

African (AFR) AF: 0.0192 AC: 641 AN: 33410

American (AMR) AF: 0.00128 AC: 57 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1110972

Other (OTH) AF: 0.00167 AC: 101 AN: 60336

GnomAD4 genome AF: 0.00534 AC: 812 AN: 152014 Hom.: 6 Cov.: 32 AF XY: 0.00518 AC XY: 385 AN XY: 74302

African (AFR) AF: 0.0169 AC: 699 AN: 41464

American (AMR) AF: 0.00628 AC: 96 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67948

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

Alfa AF: 0.00200 Hom.: 1

Bravo AF: 0.00677

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy 16 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397517288; hg19: chr4-120057671;