rs25665

Variant names:

• chr19-50454140-G-A
• rs25665
• NM_004533.4:c.1870G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50454140-G-A
• chr19-50454140-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004533.4(MYBPC2):​c.1870G>A​(p.Val624Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,612,942 control chromosomes in the GnomAD database, including 43,641 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.19 (3424 hom., cov: 30)
  • Exomes 𝑓: 0.23 (40217 hom.)
• Consequence: MYBPC2 NM_004533.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.01
• Publications: 28 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034859478).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC2	NM_004533.4	c.1870G>A	p.Val624Ile	missense_variant	Exon 17 of 28	ENST00000357701.6	NP_004524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC2	ENST00000357701.6	c.1870G>A	p.Val624Ile	missense_variant	Exon 17 of 28	1	NM_004533.4	ENSP00000350332.4

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29143 AN: 151952 Hom.: 3419 Cov.: 30

Gnomad AFR AF: 0.0656

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.220

GnomAD2 exomes AF: 0.258 AC: 63713 AN: 247216 AF XY: 0.258

Gnomad AFR exome AF: 0.0595

Gnomad AMR exome AF: 0.366

Gnomad ASJ exome AF: 0.209

Gnomad EAS exome AF: 0.390

Gnomad FIN exome AF: 0.266

Gnomad NFE exome AF: 0.224

Gnomad OTH exome AF: 0.251

GnomAD4 exome AF: 0.228 AC: 333701 AN: 1460872 Hom.: 40217 Cov.: 36 AF XY: 0.230 AC XY: 167051 AN XY: 726714

African (AFR) AF: 0.0592 AC: 1981 AN: 33472

American (AMR) AF: 0.350 AC: 15585 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 5333 AN: 26114

East Asian (EAS) AF: 0.366 AC: 14503 AN: 39660

South Asian (SAS) AF: 0.292 AC: 25137 AN: 86148

European-Finnish (FIN) AF: 0.266 AC: 14170 AN: 53332

Middle Eastern (MID) AF: 0.315 AC: 1818 AN: 5768

European-Non Finnish (NFE) AF: 0.217 AC: 241227 AN: 1111480

Other (OTH) AF: 0.231 AC: 13947 AN: 60348

GnomAD4 genome AF: 0.192 AC: 29158 AN: 152070 Hom.: 3424 Cov.: 30 AF XY: 0.199 AC XY: 14764 AN XY: 74324

African (AFR) AF: 0.0655 AC: 2720 AN: 41536

American (AMR) AF: 0.278 AC: 4240 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 709 AN: 3472

East Asian (EAS) AF: 0.385 AC: 1990 AN: 5164

South Asian (SAS) AF: 0.296 AC: 1427 AN: 4822

European-Finnish (FIN) AF: 0.270 AC: 2852 AN: 10562

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.213 AC: 14476 AN: 67958

Other (OTH) AF: 0.222 AC: 469 AN: 2110

Alfa AF: 0.213 Hom.: 12449

Bravo AF: 0.190

TwinsUK AF: 0.232 AC: 859

ALSPAC AF: 0.228 AC: 879

ESP6500AA AF: 0.0626 AC: 263

ESP6500EA AF: 0.212 AC: 1778

ExAC AF: 0.253 AC: 30609

Asia WGS AF: 0.325 AC: 1132 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.0060	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.15	N
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.0
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.086
Sift	Benign	0.15	T
Sift4G	Uncertain	0.036	D
Polyphen		0.041	B
Vest4		0.040
MPC		0.16
ClinPred		0.0080	T
GERP RS		-0.48
Varity_R		0.063
gMVP		0.24
Mutation Taster		=95/5	polymorphism (auto)

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: rs25665; hg19: chr19-50957397; COSMIC: COSV63093740;