rs181619118

Variant names:

• chr12-101614487-C-T
• rs181619118
• NM_002465.4:c.26-9C>T

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.26-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,613,710 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (15 hom., cov: 32)
  • Exomes 𝑓: 0.012 (140 hom.)
• Consequence: MYBPC1 NM_002465.4 intron
• Scores: Splicing: ADA: 0.0002864
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.237
• Publications: 2 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

LOC105369938 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 12-101614487-C-T is Benign according to our data. Variant chr12-101614487-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258662.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 = 0.0093 (1417/152310) while in subpopulation NFE AF = 0.0123 (837/68022). AF 95% confidence interval is 0.0116. There are 15 homozygotes in GnomAd4. There are 643 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC1	NM_002465.4	MANE Select	c.26-9C>T		intron	N/A	NP_002456.2
	MYBPC1	NM_001404675.1		c.26-9C>T		intron	N/A	NP_001391604.1
	MYBPC1	NM_001254718.3		c.26-9C>T		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.26-9C>T		intron	N/A	ENSP00000354849.2
	MYBPC1	ENST00000361685.6	TSL:1	c.26-9C>T		intron	N/A	ENSP00000354845.2
	MYBPC1	ENST00000545503.6	TSL:1	c.26-9C>T		intron	N/A	ENSP00000440034.2

Frequencies

GnomAD3 genomes AF: 0.00931 AC: 1417 AN: 152192 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0596

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.0102 AC: 2567 AN: 250704 AF XY: 0.0108

Gnomad AFR exome AF: 0.00241

Gnomad AMR exome AF: 0.00945

Gnomad ASJ exome AF: 0.0543

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.0149

GnomAD4 exome AF: 0.0119 AC: 17356 AN: 1461400 Hom.: 140 Cov.: 30 AF XY: 0.0118 AC XY: 8589 AN XY: 727012

African (AFR) AF: 0.00379 AC: 127 AN: 33468

American (AMR) AF: 0.00956 AC: 427 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.0545 AC: 1424 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39678

South Asian (SAS) AF: 0.00465 AC: 401 AN: 86230

European-Finnish (FIN) AF: 0.000769 AC: 41 AN: 53344

Middle Eastern (MID) AF: 0.0385 AC: 221 AN: 5742

European-Non Finnish (NFE) AF: 0.0124 AC: 13816 AN: 1111772

Other (OTH) AF: 0.0149 AC: 897 AN: 60356

GnomAD4 genome AF: 0.00930 AC: 1417 AN: 152310 Hom.: 15 Cov.: 32 AF XY: 0.00863 AC XY: 643 AN XY: 74474

African (AFR) AF: 0.00281 AC: 117 AN: 41576

American (AMR) AF: 0.0117 AC: 179 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0596 AC: 207 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0123 AC: 837 AN: 68022

Other (OTH) AF: 0.0185 AC: 39 AN: 2112

Alfa AF: 0.0134 Hom.: 14

Bravo AF: 0.00977

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0148

EpiControl AF: 0.0148

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.76
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 44

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

Other links and lift over

dbSNP: rs181619118; hg19: chr12-102008265;