10-68121455-T-C

Position:

• chr10-68121455-T-C

Variant summary

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

The NM_032578.4(MYPN):​c.17T>C​(p.Ile6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.88

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 (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=0.08652362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYPN	NM_032578.4	c.17T>C	p.Ile6Thr	missense_variant	2/20	ENST00000358913.10	NP_115967.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYPN	ENST00000358913.10	c.17T>C	p.Ile6Thr	missense_variant	2/20	1	NM_032578.4	ENSP00000351790.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250164 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135270

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460282 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726374

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1KK Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 11, 2018

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MYPN-related disease. This variant is present in population databases (rs774766927, ExAC 0.006%). This sequence change replaces isoleucine with threonine at codon 6 of the MYPN protein (p.Ile6Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2023

The p.I6T variant (also known as c.17T>C), located in coding exon 1 of the MYPN gene, results from a T to C substitution at nucleotide position 17. The isoleucine at codon 6 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	0.98
Eigen	Benign	-0.069
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.68	T;.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.087	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L;L;L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.44	N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0080	D;D;D
Sift4G	Benign	0.34	T;T;D
Polyphen		0.047	B;B;B
Vest4		0.24
MutPred		0.12		Gain of phosphorylation at I6 (P = 0.0073);Gain of phosphorylation at I6 (P = 0.0073);Gain of phosphorylation at I6 (P = 0.0073);
MVP		0.71
MPC		0.17
ClinPred		0.23	T
GERP RS		6.0
Varity_R		0.080
gMVP		0.23

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: rs774766927; hg19: chr10-69881212; COSMIC: COSV62732008;