10-68174164-G-A

Variant names:

• chr10-68174164-G-A
• rs10997975
• NM_032578.4:c.2072G>A

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.2072G>A​(p.Ser691Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,613,462 control chromosomes in the GnomAD database, including 179,292 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S691T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.39 (12983 hom., cov: 31)
  • Exomes 𝑓: 0.47 (166309 hom.)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 0.447
• Publications: 48 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=5.6671222E-5).
• BP6: Variant 10-68174164-G-A is Benign according to our data. Variant chr10-68174164-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 31797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.485 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.2072G>A	p.Ser691Asn	missense	Exon 11 of 20	NP_115967.2	Q86TC9-1
	MYPN	NM_001256267.2		c.2072G>A	p.Ser691Asn	missense	Exon 12 of 21	NP_001243196.1	Q86TC9-1
	MYPN	NM_001256268.2		c.1190G>A	p.Ser397Asn	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.2072G>A	p.Ser691Asn	missense	Exon 11 of 20	ENSP00000351790.5	Q86TC9-1
	MYPN	ENST00000540630.6	TSL:1	c.2126G>A	p.Ser709Asn	missense	Exon 11 of 20	ENSP00000441668.3	A0A8J9ASZ5
	MYPN	ENST00000613327.5	TSL:1	c.2072G>A	p.Ser691Asn	missense	Exon 12 of 21	ENSP00000480757.2	Q86TC9-1

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59819 AN: 151722 Hom.: 12985 Cov.: 31

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.419

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.392

GnomAD2 exomes AF: 0.431 AC: 108356 AN: 251472 AF XY: 0.436

Gnomad AFR exome AF: 0.205

Gnomad AMR exome AF: 0.419

Gnomad ASJ exome AF: 0.329

Gnomad EAS exome AF: 0.247

Gnomad FIN exome AF: 0.530

Gnomad NFE exome AF: 0.487

Gnomad OTH exome AF: 0.432

GnomAD4 exome AF: 0.472 AC: 690328 AN: 1461622 Hom.: 166309 Cov.: 53 AF XY: 0.472 AC XY: 343250 AN XY: 727130

African (AFR) AF: 0.201 AC: 6728 AN: 33474

American (AMR) AF: 0.417 AC: 18666 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 8523 AN: 26134

East Asian (EAS) AF: 0.313 AC: 12408 AN: 39700

South Asian (SAS) AF: 0.435 AC: 37500 AN: 86252

European-Finnish (FIN) AF: 0.526 AC: 28098 AN: 53416

Middle Eastern (MID) AF: 0.356 AC: 2056 AN: 5768

European-Non Finnish (NFE) AF: 0.495 AC: 550034 AN: 1111768

Other (OTH) AF: 0.436 AC: 26315 AN: 60388

GnomAD4 genome AF: 0.394 AC: 59850 AN: 151840 Hom.: 12983 Cov.: 31 AF XY: 0.395 AC XY: 29270 AN XY: 74192

African (AFR) AF: 0.213 AC: 8803 AN: 41414

American (AMR) AF: 0.419 AC: 6388 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1104 AN: 3466

East Asian (EAS) AF: 0.263 AC: 1353 AN: 5154

South Asian (SAS) AF: 0.431 AC: 2069 AN: 4804

European-Finnish (FIN) AF: 0.531 AC: 5572 AN: 10496

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.490 AC: 33282 AN: 67946

Other (OTH) AF: 0.392 AC: 825 AN: 2106

Alfa AF: 0.451 Hom.: 71844

Bravo AF: 0.372

TwinsUK AF: 0.497 AC: 1844

ALSPAC AF: 0.485 AC: 1869

ESP6500AA AF: 0.222 AC: 976

ESP6500EA AF: 0.480 AC: 4128

ExAC AF: 0.431 AC: 52294

Asia WGS AF: 0.322 AC: 1121 AN: 3478

EpiCase AF: 0.478

EpiControl AF: 0.469

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	Benign	0.10
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Benign	0.18
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.000057	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.45
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.042
Sift	Benign	1.0	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.067
MPC		0.12
ClinPred		0.0019	T
GERP RS		3.2
Varity_R		0.037
gMVP		0.061
Mutation Taster		=100/0	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: rs10997975; hg19: chr10-69933921; COSMIC: COSV62735061;