MYPN p.Pro1273Leu

Variant names:

• chr10-68210310-C-T
• rs148942084
• NM_032578.4:c.3818C>T
• MYPN p.Pro1273Leu

Your query was ambiguous. Multiple possible variants found:

• chr10-68210310-C-T
• chr10-68210309-CC-TT
• chr10-68210310-CG-TT
• chr10-68210310-CG-TC
• chr10-68210310-CG-TA
• chr10-68210309-CCG-TTA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_032578.4(MYPN):​c.3818C>T​(p.Pro1273Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1273T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.10
• Publications: 4 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: Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

LOC124902443 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010737121).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000249 (38/152308) while in subpopulation AFR AF = 0.000866 (36/41562). AF 95% confidence interval is 0.000643. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.3818C>T	p.Pro1273Leu	missense	Exon 20 of 20	NP_115967.2	Q86TC9-1
	MYPN	NM_001256267.2		c.3818C>T	p.Pro1273Leu	missense	Exon 21 of 21	NP_001243196.1	Q86TC9-1
	MYPN	NM_001256268.2		c.2936C>T	p.Pro979Leu	missense	Exon 24 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.3818C>T	p.Pro1273Leu	missense	Exon 20 of 20	ENSP00000351790.5	Q86TC9-1
	MYPN	ENST00000540630.6	TSL:1	c.3872C>T	p.Pro1291Leu	missense	Exon 20 of 20	ENSP00000441668.3	A0A8J9ASZ5
	MYPN	ENST00000613327.5	TSL:1	c.3818C>T	p.Pro1273Leu	missense	Exon 21 of 21	ENSP00000480757.2	Q86TC9-1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000869

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000716 AC: 18 AN: 251402 AF XY: 0.0000736

Gnomad AFR exome AF: 0.000923

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461492 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 727042

African (AFR) AF: 0.000747 AC: 25 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000183 AC: 1 AN: 5458

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1112006

Other (OTH) AF: 0.0000663 AC: 4 AN: 60350

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74482

African (AFR) AF: 0.000866 AC: 36 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

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

Alfa AF: 0.0000948 Hom.: 0

Bravo AF: 0.000276

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1KK (1)
-	1	-	Dilated cardiomyopathy 1KK;C4479186:MYPN-related myopathy (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.89
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.078
Sift	Benign	0.12	T
Sift4G	Benign	0.23	T
Varity_R		0.041
gMVP		0.14
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs148942084;

hg19: chr10-69970067;

COSMIC: COSV100589914;