rs76757102

Variant names:

• chr4-119136554-A-C
• rs76757102
• NM_016599.5:c.29A>C

Your query was ambiguous. Multiple possible variants found:

• chr4-119136554-A-C
• chr4-119136554-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016599.5(MYOZ2):​c.29A>C​(p.Gln10Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00107 in 1,613,748 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q10R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (28 hom.)
• Consequence: MYOZ2 NM_016599.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 6.79
• Publications: 9 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008525193).
• BP6: Variant 4-119136554-A-C is Benign according to our data. Variant chr4-119136554-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00125 (190/152366) while in subpopulation EAS AF = 0.0338 (175/5184). AF 95% confidence interval is 0.0297. There are 6 homozygotes in GnomAd4. There are 114 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 190 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.29A>C	p.Gln10Pro	missense	Exon 2 of 6	NP_057683.1	Q9NPC6
	MYOZ2	NM_001440645.1		c.29A>C	p.Gln10Pro	missense	Exon 2 of 7	NP_001427574.1
	MYOZ2	NM_001440646.1		c.29A>C	p.Gln10Pro	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.29A>C	p.Gln10Pro	missense	Exon 2 of 6	ENSP00000306997.6	Q9NPC6
	MYOZ2	ENST00000958711.1		c.29A>C	p.Gln10Pro	missense	Exon 2 of 7	ENSP00000628770.1
	MYOZ2	ENST00000890354.1		c.29A>C	p.Gln10Pro	missense	Exon 1 of 5	ENSP00000560413.1

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152248 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0335

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00264 AC: 662 AN: 250898 AF XY: 0.00265

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0328

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000706

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00105 AC: 1540 AN: 1461382 Hom.: 28 Cov.: 31 AF XY: 0.00109 AC XY: 793 AN XY: 726990

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26118

East Asian (EAS) AF: 0.0332 AC: 1315 AN: 39660

South Asian (SAS) AF: 0.00161 AC: 139 AN: 86246

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53406

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

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111658

Other (OTH) AF: 0.00104 AC: 63 AN: 60370

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152366 Hom.: 6 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74506

African (AFR) AF: 0.00 AC: 0 AN: 41584

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0338 AC: 175 AN: 5184

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68040

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00124 Hom.: 10

Bravo AF: 0.00173

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00266 AC: 323

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hypertrophic cardiomyopathy 16 (3)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	2.0	M
PhyloP100		6.8
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.23
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.022	D
Polyphen		0.82	P
Vest4		0.62
MVP		0.86
MPC		0.53
ClinPred		0.042	T
GERP RS		5.7
Varity_R		0.70
gMVP		0.32
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs76757102; hg19: chr4-120057709; COSMIC: COSV107397217;