rs77249928

Variant names:

• chr10-68165781-C-T
• rs77249928
• NM_032578.4:c.1563C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-68165781-C-T
• chr10-68165781-C-A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_032578.4(MYPN):​c.1563C>T​(p.Tyr521Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00043 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: MYPN NM_032578.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.86
• Publications: 0 publications found

Genes affected

MYPN (HGNC:23246): (myopalladin) Striated muscle in vertebrates comprises large proteins which must be organized properly to contract efficiently. Z-lines in striated muscle are a sign of this organization, representing the ends of actin thin filaments, titin, nebulin or nebulette and accessory proteins required for structure and function. This gene encodes a protein which interacts with nebulin in skeletal muscle or nebulette in cardiac muscle and alpha-actinin. In addition, this gene product can interact with a protein with the I-band indicating it has a regulatory as well as structural function. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]

MYPN Gene-Disease associations (from GenCC):

• MYPN-related myopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• cap myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy 1KK

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 10-68165781-C-T is Benign according to our data. Variant chr10-68165781-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.86 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00176 (268/152312) while in subpopulation AFR AF = 0.00565 (235/41580). AF 95% confidence interval is 0.00506. There are 0 homozygotes in GnomAd4. There are 128 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032578.4. 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
	MYPN	NM_032578.4	MANE Select	c.1563C>T	p.Tyr521Tyr	synonymous	Exon 9 of 20	NP_115967.2	Q86TC9-1
	MYPN	NM_001256267.2		c.1563C>T	p.Tyr521Tyr	synonymous	Exon 10 of 21	NP_001243196.1	Q86TC9-1
	MYPN	NM_001256268.2		c.681C>T	p.Tyr227Tyr	synonymous	Exon 13 of 24	NP_001243197.1	A0A087WX60

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYPN	ENST00000358913.10	TSL:1 MANE Select	c.1563C>T	p.Tyr521Tyr	synonymous	Exon 9 of 20	ENSP00000351790.5	Q86TC9-1
	MYPN	ENST00000540630.6	TSL:1	c.1617C>T	p.Tyr539Tyr	synonymous	Exon 9 of 20	ENSP00000441668.3	A0A8J9ASZ5
	MYPN	ENST00000613327.5	TSL:1	c.1563C>T	p.Tyr521Tyr	synonymous	Exon 10 of 21	ENSP00000480757.2	Q86TC9-1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00567

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000587 AC: 147 AN: 250426 AF XY: 0.000406

Gnomad AFR exome AF: 0.00555

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000291 AC: 426 AN: 1461792 Hom.: 0 Cov.: 31 AF XY: 0.000278 AC XY: 202 AN XY: 727200

African (AFR) AF: 0.00550 AC: 184 AN: 33480

American (AMR) AF: 0.000537 AC: 24 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.000786 AC: 42 AN: 53402

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000124 AC: 138 AN: 1111938

Other (OTH) AF: 0.000580 AC: 35 AN: 60394

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.00172 AC XY: 128 AN XY: 74472

African (AFR) AF: 0.00565 AC: 235 AN: 41580

American (AMR) AF: 0.000850 AC: 13 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68038

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.00190

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1KK (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.3
DANN	Benign	0.53
PhyloP100		-1.9
Mutation Taster		=100/0	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: rs77249928; hg19: chr10-69925538; COSMIC: COSV62736930; COSMIC: COSV62736930;