rs3817552

Variant names:

• chr12-101651385-C-G
• rs3817552
• NM_002465.4:c.1518C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-101651385-C-G
• chr12-101651385-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002465.4(MYBPC1):​c.1518C>G​(p.His506Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,664 control chromosomes in the GnomAD database, including 20,958 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1815 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19143 hom.)
• Consequence: MYBPC1 NM_002465.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.45
• Publications: 27 publications found

Genes affected

MYBPC1 (HGNC:7549): (myosin binding protein C1) This gene encodes a member of the myosin-binding protein C family. Myosin-binding protein C family members are myosin-associated proteins found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. The encoded protein is the slow skeletal muscle isoform of myosin-binding protein C and plays an important role in muscle contraction by recruiting muscle-type creatine kinase to myosin filaments. Mutations in this gene are associated with distal arthrogryposis type I. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

MYBPC1 Gene-Disease associations (from GenCC):

• arthrogryposis, distal, type 1B

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• myopathy, congenital, with tremor

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• lethal congenital contracture syndrome 4

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• digitotalar dysmorphism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal congenital contracture syndrome 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000257514 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017406046).
• BP6: Variant 12-101651385-C-G is Benign according to our data. Variant chr12-101651385-C-G is described in ClinVar as Benign. ClinVar VariationId is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002465.4. 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
	MYBPC1	NM_002465.4	MANE Select	c.1518C>G	p.His506Gln	missense	Exon 16 of 32	NP_002456.2
	MYBPC1	NM_001404675.1		c.1518C>G	p.His506Gln	missense	Exon 16 of 30	NP_001391604.1
	MYBPC1	NM_001254718.3		c.1443C>G	p.His481Gln	missense	Exon 14 of 30	NP_001241647.1	Q00872-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC1	ENST00000361466.7	TSL:1 MANE Select	c.1518C>G	p.His506Gln	missense	Exon 16 of 32	ENSP00000354849.2	Q00872-4
	MYBPC1	ENST00000361685.6	TSL:1	c.1518C>G	p.His506Gln	missense	Exon 16 of 31	ENSP00000354845.2	Q00872-2
	MYBPC1	ENST00000545503.6	TSL:1	c.1443C>G	p.His481Gln	missense	Exon 14 of 30	ENSP00000440034.2	Q00872-10

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22569 AN: 151980 Hom.: 1814 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.155

GnomAD2 exomes AF: 0.156 AC: 39160 AN: 251400 AF XY: 0.159

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.0803

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.293

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.158 AC: 230827 AN: 1461566 Hom.: 19143 Cov.: 33 AF XY: 0.158 AC XY: 115165 AN XY: 727088

African (AFR) AF: 0.119 AC: 3974 AN: 33468

American (AMR) AF: 0.0836 AC: 3737 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4899 AN: 26134

East Asian (EAS) AF: 0.303 AC: 12040 AN: 39690

South Asian (SAS) AF: 0.155 AC: 13343 AN: 86254

European-Finnish (FIN) AF: 0.160 AC: 8520 AN: 53410

Middle Eastern (MID) AF: 0.202 AC: 1165 AN: 5766

European-Non Finnish (NFE) AF: 0.156 AC: 173435 AN: 1111742

Other (OTH) AF: 0.161 AC: 9714 AN: 60384

GnomAD4 genome AF: 0.148 AC: 22562 AN: 152098 Hom.: 1815 Cov.: 32 AF XY: 0.149 AC XY: 11102 AN XY: 74334

African (AFR) AF: 0.127 AC: 5248 AN: 41480

American (AMR) AF: 0.105 AC: 1599 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 655 AN: 3472

East Asian (EAS) AF: 0.299 AC: 1548 AN: 5172

South Asian (SAS) AF: 0.160 AC: 769 AN: 4812

European-Finnish (FIN) AF: 0.166 AC: 1757 AN: 10576

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10510 AN: 67982

Other (OTH) AF: 0.154 AC: 324 AN: 2110

Alfa AF: 0.149 Hom.: 1438

Bravo AF: 0.144

TwinsUK AF: 0.152 AC: 562

ALSPAC AF: 0.154 AC: 593

ESP6500AA AF: 0.130 AC: 571

ESP6500EA AF: 0.148 AC: 1273

ExAC AF: 0.157 AC: 19070

Asia WGS AF: 0.204 AC: 708 AN: 3478

EpiCase AF: 0.160

EpiControl AF: 0.163

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Arthrogryposis, distal, type 1B (2)
-	-	2	not provided (2)
-	-	1	Lethal congenital contracture syndrome 4 (1)
-	-	1	Myopathy, congenital, with tremor (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Benign	0.27
Sift	Uncertain	0.012	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.67		Gain of catalytic residue at R497 (P = 0.0011)
MPC		0.76
ClinPred		0.039	T
GERP RS		3.6
Varity_R		0.58
gMVP		0.70
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3817552; hg19: chr12-102045163; COSMIC: COSV62251483; COSMIC: COSV62251483;