rs11596653

Variant names:

• chr10-68148400-T-C
• rs11596653
• NM_032578.4:c.1178T>C

Your query was ambiguous. Multiple possible variants found:

• chr10-68148400-T-C
• chr10-68148400-T-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.1178T>C​(p.Val393Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 1,613,918 control chromosomes in the GnomAD database, including 4,645 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (2326 hom., cov: 32)
  • Exomes 𝑓: 0.024 (2319 hom.)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.416
• Publications: 14 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

LOC107984240 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033382177).
• BP6: Variant 10-68148400-T-C is Benign according to our data. Variant chr10-68148400-T-C is described in ClinVar as Benign. ClinVar VariationId is 31793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 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.1178T>C	p.Val393Ala	missense	Exon 5 of 20	NP_115967.2	Q86TC9-1
	MYPN	NM_001256267.2		c.1178T>C	p.Val393Ala	missense	Exon 6 of 21	NP_001243196.1	Q86TC9-1
	MYPN	NM_001256268.2		c.296T>C	p.Val99Ala	missense	Exon 9 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.1178T>C	p.Val393Ala	missense	Exon 5 of 20	ENSP00000351790.5	Q86TC9-1
	MYPN	ENST00000540630.6	TSL:1	c.1232T>C	p.Val411Ala	missense	Exon 5 of 20	ENSP00000441668.3	A0A8J9ASZ5
	MYPN	ENST00000613327.5	TSL:1	c.1178T>C	p.Val393Ala	missense	Exon 6 of 21	ENSP00000480757.2	Q86TC9-1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15775 AN: 152070 Hom.: 2315 Cov.: 32

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0467

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0274

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0158

Gnomad OTH AF: 0.0894

GnomAD2 exomes AF: 0.0390 AC: 9797 AN: 251430 AF XY: 0.0342

Gnomad AFR exome AF: 0.333

Gnomad AMR exome AF: 0.0264

Gnomad ASJ exome AF: 0.00963

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.0316

GnomAD4 exome AF: 0.0240 AC: 35104 AN: 1461730 Hom.: 2319 Cov.: 31 AF XY: 0.0237 AC XY: 17240 AN XY: 727166

African (AFR) AF: 0.336 AC: 11234 AN: 33456

American (AMR) AF: 0.0283 AC: 1267 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00853 AC: 223 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0365 AC: 3148 AN: 86256

European-Finnish (FIN) AF: 0.0128 AC: 684 AN: 53416

Middle Eastern (MID) AF: 0.0569 AC: 328 AN: 5764

European-Non Finnish (NFE) AF: 0.0142 AC: 15814 AN: 1111890

Other (OTH) AF: 0.0398 AC: 2402 AN: 60392

GnomAD4 genome AF: 0.104 AC: 15823 AN: 152188 Hom.: 2326 Cov.: 32 AF XY: 0.101 AC XY: 7481 AN XY: 74422

African (AFR) AF: 0.326 AC: 13514 AN: 41464

American (AMR) AF: 0.0466 AC: 713 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00951 AC: 33 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0276 AC: 133 AN: 4822

European-Finnish (FIN) AF: 0.0140 AC: 149 AN: 10620

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0158 AC: 1074 AN: 68014

Other (OTH) AF: 0.0885 AC: 187 AN: 2114

Alfa AF: 0.0462 Hom.: 2285

Bravo AF: 0.116

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0140 AC: 54

ESP6500AA AF: 0.332 AC: 1464

ESP6500EA AF: 0.0147 AC: 126

ExAC AF: 0.0452 AC: 5491

Asia WGS AF: 0.0360 AC: 125 AN: 3478

EpiCase AF: 0.0183

EpiControl AF: 0.0164

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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	Benign	0.11
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.046	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.20	N
PhyloP100		0.42
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.037
Sift	Benign	0.45	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.049
MPC		0.16
ClinPred		0.0021	T
GERP RS		2.5
Varity_R		0.034
gMVP		0.16
Mutation Taster		=99/1	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: rs11596653; hg19: chr10-69908157;