4-119135991-GT-GTT

Variant names:

• chr4-119135991-G-GT
• rs58371596
• NM_016599.5:c.-15+11dupT

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.-15+11dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 164,364 control chromosomes in the GnomAD database, including 37 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (1 hom.)
• Consequence: MYOZ2 NM_016599.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.696
• Publications: 2 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 4-119135991-G-GT is Benign according to our data. Variant chr4-119135991-G-GT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 347405.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 = 0.019 (2887/152324) while in subpopulation AFR AF = 0.036 (1495/41568). AF 95% confidence interval is 0.0344. There are 36 homozygotes in GnomAd4. There are 1376 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2887 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.-15+11dupT		intron	N/A	NP_057683.1	Q9NPC6
	MYOZ2	NM_001440645.1		c.-15+11dupT		intron	N/A	NP_001427574.1
	MYOZ2	NM_001440646.1		c.-15+11dupT		intron	N/A	NP_001427575.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOZ2	ENST00000307128.6	TSL:1 MANE Select	c.-15+9_-15+10insT		intron	N/A	ENSP00000306997.6	Q9NPC6
	MYOZ2	ENST00000958711.1		c.-15+9_-15+10insT		intron	N/A	ENSP00000628770.1
	MYOZ2	ENST00000890356.1		c.-15+5_-15+6insT		splice_region intron	N/A	ENSP00000560415.1

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2883 AN: 152206 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0359

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00621

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.0162

GnomAD4 exome AF: 0.00872 AC: 105 AN: 12040 Hom.: 1 Cov.: 0 AF XY: 0.00817 AC XY: 52 AN XY: 6366

African (AFR) AF: 0.0152 AC: 1 AN: 66

American (AMR) AF: 0.00543 AC: 10 AN: 1840

Ashkenazi Jewish (ASJ) AF: 0.00676 AC: 1 AN: 148

East Asian (EAS) AF: 0.00 AC: 0 AN: 512

South Asian (SAS) AF: 0.00240 AC: 3 AN: 1250

European-Finnish (FIN) AF: 0.00331 AC: 1 AN: 302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 26

European-Non Finnish (NFE) AF: 0.0114 AC: 84 AN: 7366

Other (OTH) AF: 0.00943 AC: 5 AN: 530

GnomAD4 genome AF: 0.0190 AC: 2887 AN: 152324 Hom.: 36 Cov.: 32 AF XY: 0.0185 AC XY: 1376 AN XY: 74484

African (AFR) AF: 0.0360 AC: 1495 AN: 41568

American (AMR) AF: 0.0135 AC: 206 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4826

European-Finnish (FIN) AF: 0.00621 AC: 66 AN: 10624

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0146 AC: 995 AN: 68036

Other (OTH) AF: 0.0161 AC: 34 AN: 2116

Alfa AF: 0.0165 Hom.: 2

Bravo AF: 0.0199

Asia WGS AF: 0.00404 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 16 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.70
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: rs58371596; hg19: chr4-120057146;