19-50437671-G-T

Variant summary

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

The NM_004533.4(MYBPC2):c.525G>T(p.Lys175Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,560 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYBPC2 NM_004533.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25

Genes affected

MYBPC2 (HGNC:7550): (myosin binding protein C2) This gene encodes a member of the myosin-binding protein C family. This family includes the fast-, slow- and cardiac-type isoforms, each of which is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. The protein encoded by this locus is referred to as the fast-type isoform. Mutations in the related but distinct genes encoding the slow-type and cardiac-type isoforms have been associated with distal arthrogryposis, type 1 and hypertrophic cardiomyopathy, respectively. [provided by RefSeq, Jul 2012]

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=0.2257565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC2	NM_004533.4	c.525G>T	p.Lys175Asn	missense_variant	7/28	ENST00000357701.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC2	ENST00000357701.6	c.525G>T	p.Lys175Asn	missense_variant	7/28	1	NM_004533.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452560 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 721564

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2023

The c.525G>T (p.K175N) alteration is located in exon 7 (coding exon 7) of the MYBPC2 gene. This alteration results from a G to T substitution at nucleotide position 525, causing the lysine (K) at amino acid position 175 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	18
Dann	Benign	0.65
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.072
Sift	Benign	0.40	T
Sift4G	Benign	0.45	T
Polyphen		0.79	P
Vest4		0.16
MutPred		0.40		Loss of ubiquitination at K175 (P = 0.002);
MVP		0.74
MPC		0.21
ClinPred		0.55	D
GERP RS		1.4
Varity_R		0.13
gMVP		0.21

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: chr19-50940928;