NM_002465.4:c.103+4140A>G

Variant names:

• chr12-101621383-A-G
• rs7138495
• NM_002465.4:c.103+4140A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002465.4(MYBPC1):​c.103+4140A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 152,232 control chromosomes in the GnomAD database, including 1,477 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1477 hom., cov: 33)
• Consequence: MYBPC1 NM_002465.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.36
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC1	NM_002465.4	c.103+4140A>G		intron_variant	Intron 3 of 31	ENST00000361466.7	NP_002456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC1	ENST00000361466.7	c.103+4140A>G		intron_variant	Intron 3 of 31	1	NM_002465.4	ENSP00000354849.2
MYBPC1	ENST00000551300.5	c.-270+4140A>G		intron_variant	Intron 4 of 31	1		ENSP00000447116.1

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19494 AN: 152114 Hom.: 1477 Cov.: 33

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0847

Gnomad ASJ AF: 0.0732

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.112

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.128 AC: 19492 AN: 152232 Hom.: 1477 Cov.: 33 AF XY: 0.125 AC XY: 9338 AN XY: 74446

African (AFR) AF: 0.192 AC: 7965 AN: 41514

American (AMR) AF: 0.0845 AC: 1293 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0732 AC: 254 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5190

South Asian (SAS) AF: 0.0201 AC: 97 AN: 4828

European-Finnish (FIN) AF: 0.143 AC: 1520 AN: 10608

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8042 AN: 67998

Other (OTH) AF: 0.110 AC: 233 AN: 2110

Alfa AF: 0.123 Hom.: 301

Bravo AF: 0.128

Asia WGS AF: 0.0310 AC: 107 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	15
DANN	Benign	0.63
PhyloP100		2.4
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: rs7138495; hg19: chr12-102015161;