12-101673634-T-C

Variant names:

• chr12-101673634-T-C
• rs11110952
• NM_002465.4:c.2809+12T>C

Variant summary

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

The NM_001404675.1(MYBPC1):​c.2809+12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0264 in 1,613,996 control chromosomes in the GnomAD database, including 2,496 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (260 hom., cov: 32)
  • Exomes 𝑓: 0.026 (2236 hom.)
• Consequence: MYBPC1 NM_001404675.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0720
• Publications: 4 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=-0.83).
• BP6: Variant 12-101673634-T-C is Benign according to our data. Variant chr12-101673634-T-C is described in ClinVar as Benign. ClinVar VariationId is 258663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001404675.1. 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.2809+12T>C		intron	N/A	NP_002456.2
	MYBPC1	NM_001404675.1		c.2809+12T>C		intron	N/A	NP_001391604.1
	MYBPC1	NM_001254718.3		c.2788+12T>C		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.2809+12T>C		intron	N/A	ENSP00000354849.2
	MYBPC1	ENST00000361685.6	TSL:1	c.2809+12T>C		intron	N/A	ENSP00000354845.2
	MYBPC1	ENST00000545503.6	TSL:1	c.2734+12T>C		intron	N/A	ENSP00000440034.2

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3978 AN: 152178 Hom.: 258 Cov.: 32

Gnomad AFR AF: 0.00415

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0435

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.0296

GnomAD2 exomes AF: 0.0504 AC: 12650 AN: 250948 AF XY: 0.0519

Gnomad AFR exome AF: 0.00345

Gnomad AMR exome AF: 0.0531

Gnomad ASJ exome AF: 0.0245

Gnomad EAS exome AF: 0.272

Gnomad FIN exome AF: 0.0263

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.0344

GnomAD4 exome AF: 0.0264 AC: 38634 AN: 1461700 Hom.: 2236 Cov.: 32 AF XY: 0.0287 AC XY: 20889 AN XY: 727146

African (AFR) AF: 0.00272 AC: 91 AN: 33474

American (AMR) AF: 0.0525 AC: 2349 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0263 AC: 688 AN: 26130

East Asian (EAS) AF: 0.261 AC: 10346 AN: 39686

South Asian (SAS) AF: 0.112 AC: 9648 AN: 86240

European-Finnish (FIN) AF: 0.0236 AC: 1258 AN: 53390

Middle Eastern (MID) AF: 0.0180 AC: 104 AN: 5768

European-Non Finnish (NFE) AF: 0.0107 AC: 11885 AN: 1111908

Other (OTH) AF: 0.0375 AC: 2265 AN: 60388

GnomAD4 genome AF: 0.0262 AC: 3990 AN: 152296 Hom.: 260 Cov.: 32 AF XY: 0.0310 AC XY: 2305 AN XY: 74470

African (AFR) AF: 0.00414 AC: 172 AN: 41560

American (AMR) AF: 0.0444 AC: 680 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 104 AN: 3472

East Asian (EAS) AF: 0.249 AC: 1292 AN: 5186

South Asian (SAS) AF: 0.126 AC: 607 AN: 4822

European-Finnish (FIN) AF: 0.0259 AC: 275 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0116 AC: 792 AN: 68020

Other (OTH) AF: 0.0298 AC: 63 AN: 2114

Alfa AF: 0.0206 Hom.: 78

Bravo AF: 0.0260

Asia WGS AF: 0.169 AC: 586 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Arthrogryposis, distal, type 1B (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.48
PhyloP100		0.072
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs11110952; hg19: chr12-102067412; COSMIC: COSV104421779; COSMIC: COSV104421779;