rs138313730

Variant names:

• chr10-68199563-C-A
• rs138313730
• NM_032578.4:c.3481C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-68199563-C-A
• chr10-68199563-C-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.3481C>A​(p.Leu1161Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,607,316 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (4 hom., cov: 31)
  • Exomes 𝑓: 0.00098 (17 hom.)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:15 O:1
• Conservation: PhyloP100: 5.03
• Publications: 9 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=0.008320689).
• BP6: Variant 10-68199563-C-A is Benign according to our data. Variant chr10-68199563-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 31819.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0013 (189/145522) while in subpopulation AMR AF = 0.00775 (111/14322). AF 95% confidence interval is 0.00658. There are 4 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.3481C>A	p.Leu1161Ile	missense	Exon 17 of 20	NP_115967.2	Q86TC9-1
	MYPN	NM_001256267.2		c.3481C>A	p.Leu1161Ile	missense	Exon 18 of 21	NP_001243196.1	Q86TC9-1
	MYPN	NM_001256268.2		c.2599C>A	p.Leu867Ile	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.3481C>A	p.Leu1161Ile	missense	Exon 17 of 20	ENSP00000351790.5	Q86TC9-1
	MYPN	ENST00000540630.6	TSL:1	c.3535C>A	p.Leu1179Ile	missense	Exon 17 of 20	ENSP00000441668.3	A0A8J9ASZ5
	MYPN	ENST00000613327.5	TSL:1	c.3481C>A	p.Leu1161Ile	missense	Exon 18 of 21	ENSP00000480757.2	Q86TC9-1

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 189 AN: 145398 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000824

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00769

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00535

Gnomad SAS AF: 0.00112

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000199

Gnomad OTH AF: 0.000505

GnomAD2 exomes AF: 0.00381 AC: 957 AN: 251238 AF XY: 0.00305

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0227

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00506

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.000977 AC: 1428 AN: 1461794 Hom.: 17 Cov.: 41 AF XY: 0.000887 AC XY: 645 AN XY: 727208

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.0196 AC: 877 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00527 AC: 209 AN: 39696

South Asian (SAS) AF: 0.000754 AC: 65 AN: 86252

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000182 AC: 202 AN: 1111930

Other (OTH) AF: 0.000745 AC: 45 AN: 60394

GnomAD4 genome AF: 0.00130 AC: 189 AN: 145522 Hom.: 4 Cov.: 31 AF XY: 0.00120 AC XY: 85 AN XY: 70734

African (AFR) AF: 0.000822 AC: 33 AN: 40148

American (AMR) AF: 0.00775 AC: 111 AN: 14322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3426

East Asian (EAS) AF: 0.00516 AC: 26 AN: 5038

South Asian (SAS) AF: 0.00112 AC: 5 AN: 4456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000199 AC: 13 AN: 65278

Other (OTH) AF: 0.000500 AC: 1 AN: 2002

Alfa AF: 0.000963 Hom.: 8

Bravo AF: 0.00254

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00330 AC: 400

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	4	Dilated cardiomyopathy 1KK (6)
-	-	6	not provided (7)
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Primary dilated cardiomyopathy;C0018801:Heart failure;C0878544:Cardiomyopathy (1)
-	1	-	Primary familial dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0083	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.9	L
PhyloP100		5.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.71
Sift	Benign	0.047	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.64
MVP		0.86
MPC		0.64
ClinPred		0.038	T
GERP RS		5.4
Varity_R		0.41
gMVP		0.37
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs138313730; hg19: chr10-69959320;