rs183524782

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-101634614-A-G
• chr12-101634614-A-C

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: 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 -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

Sel.	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	Q00872-6

Ensembl Transcripts

Sel.	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	Q00872-4
	MYBPC1	ENST00000361685.6	TSL:1	c.608+9A>G		intron	N/A	ENSP00000354845.2	Q00872-2
	MYBPC1	ENST00000545503.6	TSL:1	c.533+9A>G		intron	N/A	ENSP00000440034.2	Q00872-10

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

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;