10-68121325-C-A

Variant names:

• chr10-68121325-C-A
• rs56355961
• NM_032578.4:c.-1-113C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032578.4(MYPN):​c.-1-113C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 726,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: MYPN NM_032578.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0500
• 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: Labcorp Genetics (formerly Invitae), ClinGen
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYPN	NM_032578.4	c.-1-113C>A		intron_variant	Intron 1 of 19	ENST00000358913.10	NP_115967.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYPN	ENST00000358913.10	c.-1-113C>A		intron_variant	Intron 1 of 19	1	NM_032578.4	ENSP00000351790.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000275 AC: 2 AN: 726826 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 370084

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

African (AFR) AF: 0.00 AC: 0 AN: 17152

American (AMR) AF: 0.00 AC: 0 AN: 20990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15694

East Asian (EAS) AF: 0.00 AC: 0 AN: 32544

South Asian (SAS) AF: 0.00 AC: 0 AN: 47146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2452

European-Non Finnish (NFE) AF: 0.00000390 AC: 2 AN: 512700

Other (OTH) AF: 0.00 AC: 0 AN: 34506

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.8
DANN	Benign	0.59
PhyloP100		-0.050
PromoterAI		-0.0023	Neutral

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: rs56355961; hg19: chr10-69881082;