12-101595222-C-T

Variant names:

• chr12-101595222-C-T
• rs117213476
• NM_002465.4:c.25+127C>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.25+127C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00849 in 905,520 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (40 hom.)
• Consequence: MYBPC1 NM_002465.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0800
• 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=-0.82).
• BP6: Variant 12-101595222-C-T is Benign according to our data. Variant chr12-101595222-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1212014.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 = 0.00648 (986/152070) while in subpopulation NFE AF = 0.0108 (736/67988). AF 95% confidence interval is 0.0102. There are 5 homozygotes in GnomAd4. There are 443 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.25+127C>T		intron	N/A	NP_002456.2
	MYBPC1	NM_001404675.1		c.25+127C>T		intron	N/A	NP_001391604.1
	MYBPC1	NM_001254718.3		c.25+127C>T		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.25+127C>T		intron	N/A	ENSP00000354849.2	Q00872-4
	MYBPC1	ENST00000361685.6	TSL:1	c.25+127C>T		intron	N/A	ENSP00000354845.2	Q00872-2
	MYBPC1	ENST00000545503.6	TSL:1	c.25+127C>T		intron	N/A	ENSP00000440034.2	Q00872-10

Frequencies

GnomAD3 genomes AF: 0.00649 AC: 986 AN: 151952 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00617

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00256

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.00432

GnomAD4 exome AF: 0.00889 AC: 6701 AN: 753450 Hom.: 40 AF XY: 0.00879 AC XY: 3465 AN XY: 394004

African (AFR) AF: 0.00146 AC: 27 AN: 18432

American (AMR) AF: 0.00519 AC: 163 AN: 31432

Ashkenazi Jewish (ASJ) AF: 0.000608 AC: 12 AN: 19746

East Asian (EAS) AF: 0.00 AC: 0 AN: 31932

South Asian (SAS) AF: 0.000324 AC: 20 AN: 61794

European-Finnish (FIN) AF: 0.00240 AC: 96 AN: 40038

Middle Eastern (MID) AF: 0.00153 AC: 5 AN: 3278

European-Non Finnish (NFE) AF: 0.0120 AC: 6130 AN: 510504

Other (OTH) AF: 0.00683 AC: 248 AN: 36294

GnomAD4 genome AF: 0.00648 AC: 986 AN: 152070 Hom.: 5 Cov.: 32 AF XY: 0.00596 AC XY: 443 AN XY: 74316

African (AFR) AF: 0.00217 AC: 90 AN: 41512

American (AMR) AF: 0.00616 AC: 94 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00256 AC: 27 AN: 10534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0108 AC: 736 AN: 67988

Other (OTH) AF: 0.00427 AC: 9 AN: 2106

Alfa AF: 0.00980 Hom.: 0

Bravo AF: 0.00704

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.6
DANN	Benign	0.75
PhyloP100		0.080
PromoterAI		0.029	Neutral
Mutation Taster		=100/0	polymorphism

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: rs117213476; hg19: chr12-101989000;