chr12-101642527-C-T

Variant names:

• chr12-101642527-C-T
• rs2293468
• NM_002465.4:c.774C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002465.4(MYBPC1):​c.774C>T​(p.Asp258Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,612,768 control chromosomes in the GnomAD database, including 71,493 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6643 hom., cov: 32)
  • Exomes 𝑓: 0.30 (64850 hom.)
• Consequence: MYBPC1 NM_002465.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.819
• Publications: 17 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 12-101642527-C-T is Benign according to our data. Variant chr12-101642527-C-T is described in ClinVar as Benign. ClinVar VariationId is 129647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.819 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.381 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.774C>T	p.Asp258Asp	synonymous	Exon 11 of 32	NP_002456.2
	MYBPC1	NM_001404675.1		c.774C>T	p.Asp258Asp	synonymous	Exon 11 of 30	NP_001391604.1
	MYBPC1	NM_001254718.3		c.699C>T	p.Asp233Asp	synonymous	Exon 9 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.774C>T	p.Asp258Asp	synonymous	Exon 11 of 32	ENSP00000354849.2	Q00872-4
	MYBPC1	ENST00000361685.6	TSL:1	c.774C>T	p.Asp258Asp	synonymous	Exon 11 of 31	ENSP00000354845.2	Q00872-2
	MYBPC1	ENST00000545503.6	TSL:1	c.699C>T	p.Asp233Asp	synonymous	Exon 9 of 30	ENSP00000440034.2	Q00872-10

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44391 AN: 151958 Hom.: 6640 Cov.: 32

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.292

GnomAD2 exomes AF: 0.289 AC: 71831 AN: 248652 AF XY: 0.287

Gnomad AFR exome AF: 0.288

Gnomad AMR exome AF: 0.239

Gnomad ASJ exome AF: 0.269

Gnomad EAS exome AF: 0.394

Gnomad FIN exome AF: 0.333

Gnomad NFE exome AF: 0.299

Gnomad OTH exome AF: 0.295

GnomAD4 exome AF: 0.296 AC: 432250 AN: 1460690 Hom.: 64850 Cov.: 41 AF XY: 0.294 AC XY: 213239 AN XY: 726522

African (AFR) AF: 0.280 AC: 9377 AN: 33476

American (AMR) AF: 0.241 AC: 10724 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 6957 AN: 26098

East Asian (EAS) AF: 0.390 AC: 15458 AN: 39664

South Asian (SAS) AF: 0.222 AC: 19061 AN: 86006

European-Finnish (FIN) AF: 0.333 AC: 17741 AN: 53348

Middle Eastern (MID) AF: 0.312 AC: 1800 AN: 5766

European-Non Finnish (NFE) AF: 0.300 AC: 333513 AN: 1111384

Other (OTH) AF: 0.292 AC: 17619 AN: 60366

GnomAD4 genome AF: 0.292 AC: 44408 AN: 152078 Hom.: 6643 Cov.: 32 AF XY: 0.293 AC XY: 21773 AN XY: 74316

African (AFR) AF: 0.282 AC: 11697 AN: 41482

American (AMR) AF: 0.266 AC: 4067 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 925 AN: 3470

East Asian (EAS) AF: 0.396 AC: 2039 AN: 5154

South Asian (SAS) AF: 0.231 AC: 1113 AN: 4820

European-Finnish (FIN) AF: 0.338 AC: 3573 AN: 10566

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20053 AN: 67986

Other (OTH) AF: 0.289 AC: 608 AN: 2106

Alfa AF: 0.289 Hom.: 4125

Bravo AF: 0.287

Asia WGS AF: 0.290 AC: 1008 AN: 3478

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
BayesDel_noAF	Benign	-0.36
CADD	Benign	13
DANN	Benign	0.95
PhyloP100		0.82
Mutation Taster		=98/2	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: rs2293468; hg19: chr12-102036305; COSMIC: COSV62251478; COSMIC: COSV62251478;