10-68166533-G-C

Position:

• chr10-68166533-G-C

Variant summary

Our verdict is Likely benign. Variant got -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. 12/21 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. 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -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 id is 3298138.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYPN	NM_032578.4	c.1840G>C	p.Glu614Gln	missense_variant	10/20	ENST00000358913.10	NP_115967.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYPN	ENST00000358913.10	c.1840G>C	p.Glu614Gln	missense_variant	10/20	1	NM_032578.4	ENSP00000351790	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 79

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2024

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	0.036	.;.;.;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;.
MutationTaster	Benign	0.99	N;N;N
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
Polyphen		0.94	P;P;P;.
Vest4		0.17
MutPred		0.19		Loss of phosphorylation at S612 (P = 0.1288);.;Loss of phosphorylation at S612 (P = 0.1288);.;
MVP		0.81
MPC		0.33
ClinPred		0.73	D
GERP RS		5.3
Varity_R		0.080
gMVP		0.25

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

Publications

LitVar

Other links and lift over

dbSNP: rs143338091; hg19: chr10-69926290;