rs1554842709

Positions:

• chr10-68148408-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000358913.10(MYPN):​c.1186C>G​(p.Pro396Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P396P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYPN ENST00000358913.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.492

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]

LOC107984240 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.090534866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYPN	NM_032578.4	c.1186C>G	p.Pro396Ala	missense_variant	5/20	ENST00000358913.10	NP_115967.2
LOC107984240	XR_001747479.2	n.206-1690G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYPN	ENST00000358913.10	c.1186C>G	p.Pro396Ala	missense_variant	5/20	1	NM_032578.4	ENSP00000351790	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1KK Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 08, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 544033). This variant has not been reported in the literature in individuals affected with MYPN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 396 of the MYPN protein (p.Pro396Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Benign	0.67
DEOGEN2	Benign	0.018	.;.;.;T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.63	T;T;.;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.091	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;L;.;L
MutationTaster	Benign	0.81	D;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.74	N;N;N;.;N
REVEL	Benign	0.038
Sift	Benign	0.034	D;D;D;.;T
Sift4G	Benign	0.29	T;T;T;T;T
Polyphen		0.012	B;B;B;.;B
Vest4		0.18
MutPred		0.24		Loss of catalytic residue at P396 (P = 0.0404);.;Loss of catalytic residue at P396 (P = 0.0404);.;Loss of catalytic residue at P396 (P = 0.0404);
MVP		0.50
MPC		0.13
ClinPred		0.086	T
GERP RS		0.42
Varity_R		0.035
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554842709; hg19: chr10-69908165;