chr10-68166577-C-G

Variant names:

• chr10-68166577-C-G
• rs10823148
• NM_032578.4:c.1884C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032578.4(MYPN):​c.1884C>G​(p.Phe628Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 1,613,842 control chromosomes in the GnomAD database, including 196,299 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13839 hom., cov: 31)
  • Exomes 𝑓: 0.49 (182460 hom.)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 1.71
• Publications: 40 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.222823E-4).
• BP6: Variant 10-68166577-C-G is Benign according to our data. Variant chr10-68166577-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 31804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

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.1884C>G	p.Phe628Leu	missense	Exon 10 of 20	NP_115967.2	Q86TC9-1
	MYPN	NM_001256267.2		c.1884C>G	p.Phe628Leu	missense	Exon 11 of 21	NP_001243196.1	Q86TC9-1
	MYPN	NM_001256268.2		c.1002C>G	p.Phe334Leu	missense	Exon 14 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.1884C>G	p.Phe628Leu	missense	Exon 10 of 20	ENSP00000351790.5	Q86TC9-1
	MYPN	ENST00000540630.6	TSL:1	c.1938C>G	p.Phe646Leu	missense	Exon 10 of 20	ENSP00000441668.3	A0A8J9ASZ5
	MYPN	ENST00000613327.5	TSL:1	c.1884C>G	p.Phe628Leu	missense	Exon 11 of 21	ENSP00000480757.2	Q86TC9-1

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60141 AN: 151876 Hom.: 13846 Cov.: 31

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.546

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.391

GnomAD2 exomes AF: 0.440 AC: 110543 AN: 251344 AF XY: 0.447

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.431

Gnomad ASJ exome AF: 0.328

Gnomad EAS exome AF: 0.195

Gnomad FIN exome AF: 0.544

Gnomad NFE exome AF: 0.513

Gnomad OTH exome AF: 0.443

GnomAD4 exome AF: 0.492 AC: 719955 AN: 1461848 Hom.: 182460 Cov.: 62 AF XY: 0.492 AC XY: 357766 AN XY: 727228

African (AFR) AF: 0.152 AC: 5080 AN: 33480

American (AMR) AF: 0.429 AC: 19180 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 8509 AN: 26136

East Asian (EAS) AF: 0.239 AC: 9500 AN: 39696

South Asian (SAS) AF: 0.443 AC: 38198 AN: 86258

European-Finnish (FIN) AF: 0.540 AC: 28863 AN: 53414

Middle Eastern (MID) AF: 0.343 AC: 1977 AN: 5768

European-Non Finnish (NFE) AF: 0.523 AC: 581566 AN: 1111980

Other (OTH) AF: 0.448 AC: 27082 AN: 60396

GnomAD4 genome AF: 0.396 AC: 60150 AN: 151994 Hom.: 13839 Cov.: 31 AF XY: 0.396 AC XY: 29416 AN XY: 74304

African (AFR) AF: 0.167 AC: 6928 AN: 41480

American (AMR) AF: 0.433 AC: 6612 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1089 AN: 3470

East Asian (EAS) AF: 0.211 AC: 1092 AN: 5164

South Asian (SAS) AF: 0.436 AC: 2099 AN: 4814

European-Finnish (FIN) AF: 0.546 AC: 5771 AN: 10566

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.518 AC: 35179 AN: 67928

Other (OTH) AF: 0.391 AC: 825 AN: 2112

Alfa AF: 0.475 Hom.: 13584

Bravo AF: 0.372

TwinsUK AF: 0.530 AC: 1966

ALSPAC AF: 0.512 AC: 1973

ESP6500AA AF: 0.174 AC: 768

ESP6500EA AF: 0.510 AC: 4382

ExAC AF: 0.438 AC: 53153

Asia WGS AF: 0.298 AC: 1037 AN: 3478

EpiCase AF: 0.503

EpiControl AF: 0.493

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Dilated cardiomyopathy 1KK (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	MYPN-related myopathy (1)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Benign	0.65
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.00032	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.83	L
PhyloP100		1.7
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.058
Sift	Benign	0.56	T
Sift4G	Benign	0.72	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.27		Loss of sheet (P = 0.0181)
MPC		0.16
ClinPred		0.0097	T
GERP RS		4.3
Varity_R		0.097
gMVP		0.26
Mutation Taster		=83/17	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10823148; hg19: chr10-69926334; COSMIC: COSV62734683; COSMIC: COSV62734683;