10-68109732-C-T

Variant names:

• chr10-68109732-C-T
• rs75716608
• NM_032578.4:c.-2+9C>T

Variant summary

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

The NM_032578.4(MYPN):​c.-2+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00352 in 452,758 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: MYPN NM_032578.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.47
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 10-68109732-C-T is Benign according to our data. Variant chr10-68109732-C-T is described in ClinVar as [Benign]. Clinvar id is 138420.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 = 0.00834 (1269/152228) while in subpopulation AFR AF = 0.029 (1203/41530). AF 95% confidence interval is 0.0276. There are 28 homozygotes in GnomAd4. There are 573 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYPN	NM_032578.4	c.-2+9C>T		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.-2+9C>T		intron_variant	Intron 1 of 19	1	NM_032578.4	ENSP00000351790.5

Frequencies

GnomAD3 genomes AF: 0.00834 AC: 1269 AN: 152110 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00302

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00173 AC: 223 AN: 129104 AF XY: 0.00136

Gnomad AFR exome AF: 0.0322

Gnomad AMR exome AF: 0.000742

Gnomad ASJ exome AF: 0.000124

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000614

Gnomad OTH exome AF: 0.00126

GnomAD4 exome AF: 0.00108 AC: 326 AN: 300530 Hom.: 4 Cov.: 0 AF XY: 0.000853 AC XY: 146 AN XY: 171226

African (AFR) AF: 0.0306 AC: 259 AN: 8460

American (AMR) AF: 0.000920 AC: 25 AN: 27184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10732

East Asian (EAS) AF: 0.00 AC: 0 AN: 9202

South Asian (SAS) AF: 0.0000673 AC: 4 AN: 59446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1150

European-Non Finnish (NFE) AF: 0.0000570 AC: 9 AN: 158014

Other (OTH) AF: 0.00207 AC: 29 AN: 14002

GnomAD4 genome AF: 0.00834 AC: 1269 AN: 152228 Hom.: 28 Cov.: 32 AF XY: 0.00770 AC XY: 573 AN XY: 74422

African (AFR) AF: 0.0290 AC: 1203 AN: 41530

American (AMR) AF: 0.00301 AC: 46 AN: 15272

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68026

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00516 Hom.: 2

Bravo AF: 0.00924

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 26, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dilated cardiomyopathy 1KK;C4479186:MYPN-related myopathy Benign:1

Feb 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Benign	0.77
PhyloP100		1.5
PromoterAI		-0.029	Neutral
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: rs75716608; hg19: chr10-69869489;