rs200288633

Variant names:

• chr12-101629407-ATCCTTTTCC-A
• rs200288633
• NM_002465.4:c.179-20_179-12delTCCTCCTTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002465.4(MYBPC1):​c.179-20_179-12delTCCTCCTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,491,084 control chromosomes in the GnomAD database, including 412 homozygotes. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.015 (56 hom., cov: 32)
  • Exomes 𝑓: 0.013 (356 hom.)
• Consequence: MYBPC1 NM_002465.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.84
• 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 -16 ACMG points.

• BP6: Variant 12-101629407-ATCCTTTTCC-A is Benign according to our data. Variant chr12-101629407-ATCCTTTTCC-A is described in ClinVar as Benign. ClinVar VariationId is 258659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC1	NM_002465.4	c.179-20_179-12delTCCTCCTTT		intron_variant	Intron 5 of 31	ENST00000361466.7	NP_002456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC1	ENST00000361466.7	c.179-20_179-12delTCCTCCTTT		intron_variant	Intron 5 of 31	1	NM_002465.4	ENSP00000354849.2
MYBPC1	ENST00000551300.5	c.-194-20_-194-12delTCCTCCTTT		intron_variant	Intron 6 of 31	1		ENSP00000447116.1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2216 AN: 152014 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.00278

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0735

Gnomad ASJ AF: 0.00923

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00416

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0225 AC: 5641 AN: 250656 AF XY: 0.0187

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.0192

GnomAD4 exome AF: 0.0131 AC: 17588 AN: 1338952 Hom.: 356 AF XY: 0.0123 AC XY: 8251 AN XY: 672854

African (AFR) AF: 0.00217 AC: 67 AN: 30814

American (AMR) AF: 0.108 AC: 4829 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.00563 AC: 143 AN: 25400

East Asian (EAS) AF: 0.00 AC: 0 AN: 39122

South Asian (SAS) AF: 0.00404 AC: 338 AN: 83704

European-Finnish (FIN) AF: 0.0129 AC: 681 AN: 52638

Middle Eastern (MID) AF: 0.00324 AC: 18 AN: 5556

European-Non Finnish (NFE) AF: 0.0109 AC: 10888 AN: 1000728

Other (OTH) AF: 0.0111 AC: 624 AN: 56460

GnomAD4 genome AF: 0.0146 AC: 2220 AN: 152132 Hom.: 56 Cov.: 32 AF XY: 0.0159 AC XY: 1184 AN XY: 74370

African (AFR) AF: 0.00277 AC: 115 AN: 41528

American (AMR) AF: 0.0737 AC: 1125 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00923 AC: 32 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00417 AC: 20 AN: 4798

European-Finnish (FIN) AF: 0.0112 AC: 119 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0105 AC: 712 AN: 67984

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.0118 Hom.: 1

Bravo AF: 0.0195

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Nov 15, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
BranchPoint Hunter		3.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs200288633; hg19: chr12-102023185;