12-101632148-C-G

Variant names:

• chr12-101632148-C-G
• rs61935677
• NM_002465.4:c.556+10C>G

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.556+10C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,563,424 control chromosomes in the GnomAD database, including 33,982 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3278 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30704 hom.)
• Consequence: MYBPC1 NM_001404675.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.167
• Publications: 8 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 12-101632148-C-G is Benign according to our data. Variant chr12-101632148-C-G is described in ClinVar as Benign. ClinVar VariationId is 129646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.243 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.556+10C>G		intron	N/A	NP_002456.2
	MYBPC1	NM_001404675.1		c.556+10C>G		intron	N/A	NP_001391604.1
	MYBPC1	NM_001254718.3		c.481+10C>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.556+10C>G		intron	N/A	ENSP00000354849.2
	MYBPC1	ENST00000361685.6	TSL:1	c.556+10C>G		intron	N/A	ENSP00000354845.2
	MYBPC1	ENST00000545503.6	TSL:1	c.481+10C>G		intron	N/A	ENSP00000440034.2

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30849 AN: 151904 Hom.: 3280 Cov.: 32

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.274

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.216

GnomAD2 exomes AF: 0.187 AC: 47004 AN: 251438 AF XY: 0.194

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.282

Gnomad EAS exome AF: 0.0845

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.204 AC: 287531 AN: 1411402 Hom.: 30704 Cov.: 26 AF XY: 0.206 AC XY: 145542 AN XY: 705034

African (AFR) AF: 0.230 AC: 7445 AN: 32424

American (AMR) AF: 0.127 AC: 5648 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 7388 AN: 25850

East Asian (EAS) AF: 0.0874 AC: 3450 AN: 39458

South Asian (SAS) AF: 0.260 AC: 22135 AN: 85218

European-Finnish (FIN) AF: 0.118 AC: 6319 AN: 53396

Middle Eastern (MID) AF: 0.319 AC: 1811 AN: 5680

European-Non Finnish (NFE) AF: 0.207 AC: 220811 AN: 1065958

Other (OTH) AF: 0.213 AC: 12524 AN: 58776

GnomAD4 genome AF: 0.203 AC: 30854 AN: 152022 Hom.: 3278 Cov.: 32 AF XY: 0.198 AC XY: 14697 AN XY: 74314

African (AFR) AF: 0.235 AC: 9756 AN: 41438

American (AMR) AF: 0.165 AC: 2529 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 991 AN: 3470

East Asian (EAS) AF: 0.104 AC: 539 AN: 5178

South Asian (SAS) AF: 0.255 AC: 1230 AN: 4818

European-Finnish (FIN) AF: 0.107 AC: 1128 AN: 10558

Middle Eastern (MID) AF: 0.267 AC: 78 AN: 292

European-Non Finnish (NFE) AF: 0.205 AC: 13930 AN: 67964

Other (OTH) AF: 0.217 AC: 457 AN: 2110

Alfa AF: 0.154 Hom.: 431

Bravo AF: 0.205

Asia WGS AF: 0.166 AC: 577 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Arthrogryposis, distal, type 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.0
DANN	Benign	0.51
PhyloP100		-0.17
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: rs61935677; hg19: chr12-102025926; COSMIC: COSV62253354; COSMIC: COSV62253354;