12-101634614-A-G

Variant names:

• chr12-101634614-A-G
• rs183524782
• NM_002465.4:c.608+9A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002465.4(MYBPC1):​c.608+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00575 in 1,607,052 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0059 (41 hom.)
• Consequence: MYBPC1 NM_002465.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.550
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• digitotalar dysmorphism

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 12-101634614-A-G is Benign according to our data. Variant chr12-101634614-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00425 (648/152380) while in subpopulation NFE AF = 0.00623 (424/68038). AF 95% confidence interval is 0.00574. There are 3 homozygotes in GnomAd4. There are 340 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC1	NM_002465.4	MANE Select	c.608+9A>G		intron	N/A	NP_002456.2
	MYBPC1	NM_001404675.1		c.608+9A>G		intron	N/A	NP_001391604.1
	MYBPC1	NM_001254718.3		c.533+9A>G		intron	N/A	NP_001241647.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC1	ENST00000361466.7	TSL:1 MANE Select	c.608+9A>G		intron	N/A	ENSP00000354849.2
	MYBPC1	ENST00000361685.6	TSL:1	c.608+9A>G		intron	N/A	ENSP00000354845.2
	MYBPC1	ENST00000545503.6	TSL:1	c.533+9A>G		intron	N/A	ENSP00000440034.2

Frequencies

GnomAD3 genomes AF: 0.00426 AC: 648 AN: 152262 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00549

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00623

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00405 AC: 1018 AN: 251252 AF XY: 0.00437

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00473

Gnomad NFE exome AF: 0.00592

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00590 AC: 8585 AN: 1454672 Hom.: 41 Cov.: 28 AF XY: 0.00591 AC XY: 4278 AN XY: 724198

African (AFR) AF: 0.000841 AC: 28 AN: 33298

American (AMR) AF: 0.00277 AC: 124 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00356 AC: 93 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00261 AC: 225 AN: 86108

European-Finnish (FIN) AF: 0.00468 AC: 249 AN: 53228

Middle Eastern (MID) AF: 0.00799 AC: 46 AN: 5758

European-Non Finnish (NFE) AF: 0.00682 AC: 7543 AN: 1105694

Other (OTH) AF: 0.00460 AC: 277 AN: 60168

GnomAD4 genome AF: 0.00425 AC: 648 AN: 152380 Hom.: 3 Cov.: 31 AF XY: 0.00456 AC XY: 340 AN XY: 74524

African (AFR) AF: 0.00125 AC: 52 AN: 41588

American (AMR) AF: 0.00549 AC: 84 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4834

European-Finnish (FIN) AF: 0.00452 AC: 48 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00623 AC: 424 AN: 68038

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00518 Hom.: 4

Bravo AF: 0.00420

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Aug 18, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 04, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arthrogryposis, distal, type 1B Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.1
DANN	Benign	0.84
PhyloP100		0.55
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs183524782; hg19: chr12-102028392;