10-68143056-C-G

Position:

• chr10-68143056-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_032578.4(MYPN):​c.1019C>G​(p.Ser340Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.83

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 -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYPN	NM_032578.4	c.1019C>G	p.Ser340Cys	missense_variant	3/20	ENST00000358913.10	NP_115967.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYPN	ENST00000358913.10	c.1019C>G	p.Ser340Cys	missense_variant	3/20	1	NM_032578.4	ENSP00000351790	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251092 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135694

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727222

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.000119

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

Jul 10, 2023

This variant has not been reported in the literature in individuals affected with MYPN-related conditions. This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 340 of the MYPN protein (p.Ser340Cys). This variant is present in population databases (rs777080663, gnomAD 0.003%). ClinVar contains an entry for this variant (Variation ID: 1359354). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 2023

The p.S340C variant (also known as c.1019C>G), located in coding exon 2 of the MYPN gene, results from a C to G substitution at nucleotide position 1019. The serine at codon 340 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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	0.30
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.040	.;.;.;T;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.74	T;T;.;T;T
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D
MetaSVM	Uncertain	0.015	D
MutationAssessor	Uncertain	2.1	M;.;M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.7	N;N;N;.;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.029	D;T;D;.;D
Sift4G	Uncertain	0.058	T;T;T;T;D
Polyphen		1.0	D;D;D;.;D
Vest4		0.82
MutPred		0.67		Loss of disorder (P = 0.07);.;Loss of disorder (P = 0.07);.;Loss of disorder (P = 0.07);
MVP		0.88
MPC		0.60
ClinPred		0.86	D
GERP RS		5.6
Varity_R		0.30
gMVP		0.70

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: rs777080663; hg19: chr10-69902813;