NM_004533.4:c.121G>A

Variant names:

• chr19-50435787-G-A
• rs374389710
• NM_004533.4:c.121G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004533.4(MYBPC2):​c.121G>A​(p.Glu41Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,609,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. E41Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: MYBPC2 NM_004533.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13
• Publications: 4 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12106156).

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.121G>A	p.Glu41Lys	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.121G>A	p.Glu41Lys	missense	Exon 3 of 28	ENSP00000350332.4	Q14324
	MYBPC2	ENST00000966357.1		c.121G>A	p.Glu41Lys	missense	Exon 3 of 28	ENSP00000636416.1
	MYBPC2	ENST00000966353.1		c.250G>A	p.Glu84Lys	missense	Exon 4 of 29	ENSP00000636412.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000200 AC: 49 AN: 244532 AF XY: 0.000173

Gnomad AFR exome AF: 0.0000678

Gnomad AMR exome AF: 0.000498

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000154

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000117 AC: 171 AN: 1457740 Hom.: 0 Cov.: 31 AF XY: 0.000137 AC XY: 99 AN XY: 724438

African (AFR) AF: 0.0000300 AC: 1 AN: 33388

American (AMR) AF: 0.000405 AC: 18 AN: 44450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.000362 AC: 31 AN: 85732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53240

Middle Eastern (MID) AF: 0.000869 AC: 5 AN: 5752

European-Non Finnish (NFE) AF: 0.0000847 AC: 94 AN: 1109486

Other (OTH) AF: 0.000366 AC: 22 AN: 60094

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68038

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.0000988 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.000266 AC: 1

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000207 AC: 25

EpiCase AF: 0.0000545

EpiControl AF: 0.000297

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	0.097
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0050	T
Eigen	Benign	-0.069
Eigen_PC	Benign	-0.045
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.14
Sift	Benign	0.094	T
Sift4G	Benign	0.17	T
Polyphen		0.91	P
Vest4		0.33
MVP		0.75
MPC		0.16
ClinPred		0.041	T
GERP RS		4.6
Varity_R		0.19
gMVP		0.23
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs374389710; hg19: chr19-50939044; COSMIC: COSV63100142; COSMIC: COSV63100142;