rs62620248

Variant names:

• chr10-68174502-G-A
• rs62620248
• NM_032578.4:c.2410G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-68174502-G-A
• chr10-68174502-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032578.4(MYPN):​c.2410G>A​(p.Gly804Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,613,978 control chromosomes in the GnomAD database, including 656 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G804G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (33 hom., cov: 32)
  • Exomes 𝑓: 0.026 (623 hom.)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 2.15
• Publications: 13 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=0.0081009865).
• BP6: Variant 10-68174502-G-A is Benign according to our data. Variant chr10-68174502-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 31809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0181 (2749/152144) while in subpopulation NFE AF = 0.0285 (1936/68006). AF 95% confidence interval is 0.0274. There are 33 homozygotes in GnomAd4. There are 1224 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 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.2410G>A	p.Gly804Arg	missense	Exon 11 of 20	NP_115967.2	Q86TC9-1
	MYPN	NM_001256267.2		c.2410G>A	p.Gly804Arg	missense	Exon 12 of 21	NP_001243196.1	Q86TC9-1
	MYPN	NM_001256268.2		c.1528G>A	p.Gly510Arg	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.2410G>A	p.Gly804Arg	missense	Exon 11 of 20	ENSP00000351790.5	Q86TC9-1
	MYPN	ENST00000540630.6	TSL:1	c.2464G>A	p.Gly822Arg	missense	Exon 11 of 20	ENSP00000441668.3	A0A8J9ASZ5
	MYPN	ENST00000613327.5	TSL:1	c.2410G>A	p.Gly804Arg	missense	Exon 12 of 21	ENSP00000480757.2	Q86TC9-1

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2749 AN: 152026 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00503

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0285

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0183 AC: 4584 AN: 251128 AF XY: 0.0181

Gnomad AFR exome AF: 0.00443

Gnomad AMR exome AF: 0.0139

Gnomad ASJ exome AF: 0.0261

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.0290

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0260 AC: 38079 AN: 1461834 Hom.: 623 Cov.: 37 AF XY: 0.0255 AC XY: 18567 AN XY: 727216

African (AFR) AF: 0.00418 AC: 140 AN: 33480

American (AMR) AF: 0.0150 AC: 671 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0273 AC: 713 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39690

South Asian (SAS) AF: 0.00444 AC: 383 AN: 86252

European-Finnish (FIN) AF: 0.0114 AC: 610 AN: 53418

Middle Eastern (MID) AF: 0.0180 AC: 104 AN: 5768

European-Non Finnish (NFE) AF: 0.0306 AC: 33999 AN: 1111976

Other (OTH) AF: 0.0241 AC: 1455 AN: 60396

GnomAD4 genome AF: 0.0181 AC: 2749 AN: 152144 Hom.: 33 Cov.: 32 AF XY: 0.0165 AC XY: 1224 AN XY: 74404

African (AFR) AF: 0.00501 AC: 208 AN: 41506

American (AMR) AF: 0.0208 AC: 318 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 109 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00374 AC: 18 AN: 4816

European-Finnish (FIN) AF: 0.0103 AC: 109 AN: 10584

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0285 AC: 1936 AN: 68006

Other (OTH) AF: 0.0157 AC: 33 AN: 2108

Alfa AF: 0.0243 Hom.: 113

Bravo AF: 0.0180

TwinsUK AF: 0.0345 AC: 128

ALSPAC AF: 0.0267 AC: 103

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0350 AC: 301

ExAC AF: 0.0184 AC: 2231

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0278

EpiControl AF: 0.0306

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Dilated cardiomyopathy 1KK (3)
-	-	2	not provided (3)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M
PhyloP100		2.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.086
Sift	Benign	0.042	D
Sift4G	Benign	0.56	T
Polyphen		0.92	P
Vest4		0.39
MutPred		0.32		Loss of glycosylation at S803 (P = 0.0747)
MPC		0.17
ClinPred		0.019	T
GERP RS		5.8
Varity_R		0.11
gMVP		0.35
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs62620248; hg19: chr10-69934259; COSMIC: COSV107444966;