10-68199417-C-T

Variant names:

• chr10-68199417-C-T
• rs71534278
• NM_032578.4:c.3335C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_032578.4(MYPN):​c.3335C>T​(p.Pro1112Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00241 in 1,614,168 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts 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. P1112H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (14 hom.)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2 B:17 O:1
• Conservation: PhyloP100: 6.01
• Publications: 28 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010449231).
• BP6: Variant 10-68199417-C-T is Benign according to our data. Variant chr10-68199417-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 31791.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00249 (379/152322) while in subpopulation SAS AF = 0.00517 (25/4832). AF 95% confidence interval is 0.00407. There are 3 homozygotes in GnomAd4. There are 198 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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.3335C>T	p.Pro1112Leu	missense	Exon 17 of 20	NP_115967.2	Q86TC9-1
	MYPN	NM_001256267.2		c.3335C>T	p.Pro1112Leu	missense	Exon 18 of 21	NP_001243196.1	Q86TC9-1
	MYPN	NM_001256268.2		c.2453C>T	p.Pro818Leu	missense	Exon 21 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.3335C>T	p.Pro1112Leu	missense	Exon 17 of 20	ENSP00000351790.5	Q86TC9-1
	MYPN	ENST00000540630.6	TSL:1	c.3389C>T	p.Pro1130Leu	missense	Exon 17 of 20	ENSP00000441668.3	A0A8J9ASZ5
	MYPN	ENST00000613327.5	TSL:1	c.3335C>T	p.Pro1112Leu	missense	Exon 18 of 21	ENSP00000480757.2	Q86TC9-1

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 377 AN: 152204 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00223

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00318 AC: 800 AN: 251290 AF XY: 0.00359

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00361

Gnomad ASJ exome AF: 0.00973

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00277

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00240 AC: 3509 AN: 1461846 Hom.: 14 Cov.: 35 AF XY: 0.00254 AC XY: 1849 AN XY: 727222

African (AFR) AF: 0.00170 AC: 57 AN: 33478

American (AMR) AF: 0.00380 AC: 170 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00999 AC: 261 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.00605 AC: 522 AN: 86258

European-Finnish (FIN) AF: 0.000655 AC: 35 AN: 53412

Middle Eastern (MID) AF: 0.0246 AC: 142 AN: 5766

European-Non Finnish (NFE) AF: 0.00187 AC: 2082 AN: 1111996

Other (OTH) AF: 0.00394 AC: 238 AN: 60388

GnomAD4 genome AF: 0.00249 AC: 379 AN: 152322 Hom.: 3 Cov.: 32 AF XY: 0.00266 AC XY: 198 AN XY: 74484

African (AFR) AF: 0.00128 AC: 53 AN: 41568

American (AMR) AF: 0.00497 AC: 76 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3472

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

South Asian (SAS) AF: 0.00517 AC: 25 AN: 4832

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10614

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00223 AC: 152 AN: 68036

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00282 Hom.: 2

Bravo AF: 0.00250

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00303 AC: 368

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00421

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not specified (7)
-	-	5	not provided (6)
2	-	2	Dilated cardiomyopathy 1KK (4)
-	-	2	Primary dilated cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
1	-	-	Familial hypertrophic cardiomyopathy 22 (1)
-	1	-	Hypertrophic cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.2	L
PhyloP100		6.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.45
Sift	Benign	0.053	T
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.54
MVP		0.82
MPC		0.62
ClinPred		0.021	T
GERP RS		5.4
Varity_R		0.41
gMVP		0.49
Mutation Taster		=80/20	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

Other links and lift over

dbSNP: rs71534278; hg19: chr10-69959174; COSMIC: COSV105250959;