chr10-68199581-G-A

Variant names:

• chr10-68199581-G-A
• rs750903219
• NM_032578.4:c.3493+6G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_032578.4(MYPN):​c.3493+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000885 in 1,582,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: MYPN NM_032578.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001563
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.162
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 10-68199581-G-A is Benign according to our data. Variant chr10-68199581-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 380682.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00000684 (10/1461010) while in subpopulation AFR AF = 0.000179 (6/33466). AF 95% confidence interval is 0.0000771. There are 0 homozygotes in GnomAdExome4. There are 7 alleles in the male GnomAdExome4 subpopulation. Median coverage is 40. 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYPN	NM_032578.4	MANE Select	c.3493+6G>A		splice_region intron	N/A	NP_115967.2
	MYPN	NM_001256267.2		c.3493+6G>A		splice_region intron	N/A	NP_001243196.1
	MYPN	NM_001256268.2		c.2611+6G>A		splice_region intron	N/A	NP_001243197.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYPN	ENST00000358913.10	TSL:1 MANE Select	c.3493+6G>A		splice_region intron	N/A	ENSP00000351790.5
	MYPN	ENST00000540630.6	TSL:1	c.3547+6G>A		splice_region intron	N/A	ENSP00000441668.3
	MYPN	ENST00000613327.5	TSL:1	c.3493+6G>A		splice_region intron	N/A	ENSP00000480757.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 4 AN: 121732 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000496 AC: 1 AN: 201692 AF XY: 0.00000921

Gnomad AFR exome AF: 0.0000680

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461010 Hom.: 0 Cov.: 40 AF XY: 0.00000963 AC XY: 7 AN XY: 726846

African (AFR) AF: 0.000179 AC: 6 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111224

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome AF: 0.0000329 AC: 4 AN: 121732 Hom.: 0 Cov.: 30 AF XY: 0.0000169 AC XY: 1 AN XY: 59202

African (AFR) AF: 0.000109 AC: 4 AN: 36568

American (AMR) AF: 0.00 AC: 0 AN: 12128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3084

East Asian (EAS) AF: 0.00 AC: 0 AN: 4780

South Asian (SAS) AF: 0.00 AC: 0 AN: 3748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 51266

Other (OTH) AF: 0.00 AC: 0 AN: 1698

Alfa AF: 0.0000247 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 01, 2015

GeneDx

Significance: Likely 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 Uncertain:1

Aug 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	14
DANN	Benign	0.60
PhyloP100		-0.16

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.0
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: rs750903219; hg19: chr10-69959338;