10-68166533-G-C

Variant names:

• chr10-68166533-G-C
• rs143338091
• NM_032578.4:c.1840G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_032578.4(MYPN):​c.1840G>C​(p.Glu614Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 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. E614K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.04
• Publications: 4 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: Labcorp Genetics (formerly Invitae), ClinGen
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21798721).
• BP6: Variant 10-68166533-G-C is Benign according to our data. Variant chr10-68166533-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3298138.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYPN	NM_032578.4	c.1840G>C	p.Glu614Gln	missense_variant	Exon 10 of 20	ENST00000358913.10	NP_115967.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYPN	ENST00000358913.10	c.1840G>C	p.Glu614Gln	missense_variant	Exon 10 of 20	1	NM_032578.4	ENSP00000351790.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 79

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Benign:1

May 06, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;.;.;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.87	D;D;.;D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.3	M;.;M;.
PhyloP100		4.0
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.50	N;N;N;.
REVEL	Benign	0.15
Sift	Benign	0.18	T;T;T;.
Sift4G	Benign	0.31	T;T;T;T
Vest4		0.17
ClinPred		0.73	D
GERP RS		5.3
Varity_R		0.080
gMVP		0.25
Mutation Taster		=87/13	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: rs143338091; hg19: chr10-69926290;