10-68121461-C-T

Position:

• chr10-68121461-C-T

Variant summary

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

The NM_032578.4(MYPN):​c.23C>T​(p.Ala8Val) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A8P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.44

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 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=0.23744619).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYPN	NM_032578.4	c.23C>T	p.Ala8Val	missense_variant	2/20	ENST00000358913.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYPN	ENST00000358913.10	c.23C>T	p.Ala8Val	missense_variant	2/20	1	NM_032578.4	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

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 23, 2020

The p.A8V variant (also known as c.23C>T), located in coding exon 1 of the MYPN gene, results from a C to T substitution at nucleotide position 23. The alanine at codon 8 is replaced by valine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. 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	0.32
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T;.;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.58	N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.021	D;D;D
Sift4G	Benign	0.30	T;T;T
Polyphen		0.48	P;P;P
Vest4		0.38
MutPred		0.064		Loss of glycosylation at S9 (P = 0.1561);Loss of glycosylation at S9 (P = 0.1561);Loss of glycosylation at S9 (P = 0.1561);
MVP		0.77
MPC		0.19
ClinPred		0.84	D
GERP RS		6.0
Varity_R		0.11
gMVP		0.40

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-69881218;