10-68174501-C-G

Variant names:

• chr10-68174501-C-G
• rs3814182
• NM_032578.4:c.2409C>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.2409C>G​(p.Ser803Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 1,613,720 control chromosomes in the GnomAD database, including 243,329 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S803N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.52 (20749 hom., cov: 31)
  • Exomes 𝑓: 0.55 (222580 hom.)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -3.22
• Publications: 38 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=2.4887882E-5).
• BP6: Variant 10-68174501-C-G is Benign according to our data. Variant chr10-68174501-C-G is described in ClinVar as Benign. ClinVar VariationId is 31808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.554 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.2409C>G	p.Ser803Arg	missense	Exon 11 of 20	NP_115967.2	Q86TC9-1
	MYPN	NM_001256267.2		c.2409C>G	p.Ser803Arg	missense	Exon 12 of 21	NP_001243196.1	Q86TC9-1
	MYPN	NM_001256268.2		c.1527C>G	p.Ser509Arg	missense	Exon 15 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.2409C>G	p.Ser803Arg	missense	Exon 11 of 20	ENSP00000351790.5	Q86TC9-1
	MYPN	ENST00000540630.6	TSL:1	c.2463C>G	p.Ser821Arg	missense	Exon 11 of 20	ENSP00000441668.3	A0A8J9ASZ5
	MYPN	ENST00000613327.5	TSL:1	c.2409C>G	p.Ser803Arg	missense	Exon 12 of 21	ENSP00000480757.2	Q86TC9-1

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78601 AN: 151766 Hom.: 20728 Cov.: 31

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.411

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.634

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.523

GnomAD2 exomes AF: 0.519 AC: 130288 AN: 251198 AF XY: 0.522

Gnomad AFR exome AF: 0.460

Gnomad AMR exome AF: 0.463

Gnomad ASJ exome AF: 0.430

Gnomad EAS exome AF: 0.367

Gnomad FIN exome AF: 0.631

Gnomad NFE exome AF: 0.557

Gnomad OTH exome AF: 0.512

GnomAD4 exome AF: 0.549 AC: 802859 AN: 1461836 Hom.: 222580 Cov.: 81 AF XY: 0.549 AC XY: 399092 AN XY: 727222

African (AFR) AF: 0.455 AC: 15233 AN: 33480

American (AMR) AF: 0.468 AC: 20928 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 11212 AN: 26136

East Asian (EAS) AF: 0.349 AC: 13845 AN: 39694

South Asian (SAS) AF: 0.513 AC: 44243 AN: 86256

European-Finnish (FIN) AF: 0.622 AC: 33203 AN: 53412

Middle Eastern (MID) AF: 0.462 AC: 2662 AN: 5766

European-Non Finnish (NFE) AF: 0.566 AC: 629498 AN: 1111972

Other (OTH) AF: 0.530 AC: 32035 AN: 60396

GnomAD4 genome AF: 0.518 AC: 78668 AN: 151884 Hom.: 20749 Cov.: 31 AF XY: 0.518 AC XY: 38447 AN XY: 74230

African (AFR) AF: 0.458 AC: 18979 AN: 41396

American (AMR) AF: 0.502 AC: 7657 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 1468 AN: 3470

East Asian (EAS) AF: 0.368 AC: 1900 AN: 5168

South Asian (SAS) AF: 0.513 AC: 2470 AN: 4816

European-Finnish (FIN) AF: 0.634 AC: 6682 AN: 10540

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.558 AC: 37924 AN: 67926

Other (OTH) AF: 0.524 AC: 1102 AN: 2104

Alfa AF: 0.449 Hom.: 2259

Bravo AF: 0.502

TwinsUK AF: 0.559 AC: 2072

ALSPAC AF: 0.564 AC: 2174

ESP6500AA AF: 0.468 AC: 2064

ESP6500EA AF: 0.551 AC: 4738

ExAC AF: 0.520 AC: 63155

Asia WGS AF: 0.432 AC: 1505 AN: 3478

EpiCase AF: 0.551

EpiControl AF: 0.541

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1KK (1)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	1.2
DANN	Benign	0.97
DEOGEN2	Benign	0.032	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.000025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-3.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.17
Sift	Uncertain	0.020	D
Sift4G	Benign	0.34	T
Polyphen		0.66	P
Vest4		0.38
MutPred		0.20		Loss of glycosylation at S803 (P = 0.0377)
MPC		0.39
ClinPred		0.039	T
GERP RS		-9.6
Varity_R		0.32
gMVP		0.31
Mutation Taster		=85/15	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs3814182; hg19: chr10-69934258; COSMIC: COSV62734695;