rs749073832

Variant names:

• chr19-50435859-A-T
• rs749073832
• NM_004533.4:c.193A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004533.4(MYBPC2):​c.193A>T​(p.Thr65Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,590,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: MYBPC2 NM_004533.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.893
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018422306).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004533.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC2	NM_004533.4	MANE Select	c.193A>T	p.Thr65Ser	missense	Exon 3 of 28	NP_004524.3	A0A140VJQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC2	ENST00000357701.6	TSL:1 MANE Select	c.193A>T	p.Thr65Ser	missense	Exon 3 of 28	ENSP00000350332.4	Q14324
	MYBPC2	ENST00000966357.1		c.193A>T	p.Thr65Ser	missense	Exon 3 of 28	ENSP00000636416.1
	MYBPC2	ENST00000966353.1		c.322A>T	p.Thr108Ser	missense	Exon 4 of 29	ENSP00000636412.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000126 AC: 26 AN: 206688 AF XY: 0.000161

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000500 AC: 72 AN: 1438682 Hom.: 0 Cov.: 32 AF XY: 0.0000743 AC XY: 53 AN XY: 713290

African (AFR) AF: 0.00 AC: 0 AN: 32958

American (AMR) AF: 0.00 AC: 0 AN: 41772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25610

East Asian (EAS) AF: 0.00 AC: 0 AN: 38720

South Asian (SAS) AF: 0.000848 AC: 70 AN: 82564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51888

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099920

Other (OTH) AF: 0.0000168 AC: 1 AN: 59510

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74416

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000915 AC: 11

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.77
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.74
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
PhyloP100		0.89
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.028
Sift	Benign	0.51	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.093
MutPred		0.21		Gain of phosphorylation at T65 (P = 0.0662)
MVP		0.42
MPC		0.12
ClinPred		0.0083	T
GERP RS		1.2
Varity_R		0.039
gMVP		0.044
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs749073832; hg19: chr19-50939116;