rs3835190

Variant names:

• chr12-101653096-AC-A
• rs3835190
• NM_002465.4:c.1634-18delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002465.4(MYBPC1):​c.1634-18delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,610,676 control chromosomes in the GnomAD database, including 57,525 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3990 hom., cov: 25)
  • Exomes 𝑓: 0.27 (53535 hom.)
• Consequence: MYBPC1 NM_002465.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.895
• Publications: 3 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

ENSG00000257514 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-101653096-AC-A is Benign according to our data. Variant chr12-101653096-AC-A is described in ClinVar as Benign. ClinVar VariationId is 258658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC1	NM_002465.4	c.1634-18delC		intron_variant	Intron 17 of 31	ENST00000361466.7	NP_002456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC1	ENST00000361466.7	c.1634-18delC		intron_variant	Intron 17 of 31	1	NM_002465.4	ENSP00000354849.2
MYBPC1	ENST00000551300.5	c.1262-18delC		intron_variant	Intron 18 of 31	1		ENSP00000447116.1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33631 AN: 151974 Hom.: 3992 Cov.: 25

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.229

GnomAD2 exomes AF: 0.224 AC: 56156 AN: 250220 AF XY: 0.231

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.140

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.0792

Gnomad FIN exome AF: 0.238

Gnomad NFE exome AF: 0.275

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.265 AC: 386654 AN: 1458584 Hom.: 53535 Cov.: 26 AF XY: 0.265 AC XY: 192262 AN XY: 725802

African (AFR) AF: 0.143 AC: 4793 AN: 33450

American (AMR) AF: 0.144 AC: 6458 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 7868 AN: 26116

East Asian (EAS) AF: 0.0890 AC: 3533 AN: 39688

South Asian (SAS) AF: 0.229 AC: 19768 AN: 86208

European-Finnish (FIN) AF: 0.240 AC: 12614 AN: 52598

Middle Eastern (MID) AF: 0.321 AC: 1847 AN: 5762

European-Non Finnish (NFE) AF: 0.283 AC: 314176 AN: 1109764

Other (OTH) AF: 0.259 AC: 15597 AN: 60298

GnomAD4 genome AF: 0.221 AC: 33627 AN: 152092 Hom.: 3990 Cov.: 25 AF XY: 0.217 AC XY: 16157 AN XY: 74360

African (AFR) AF: 0.144 AC: 5962 AN: 41502

American (AMR) AF: 0.189 AC: 2896 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1059 AN: 3470

East Asian (EAS) AF: 0.101 AC: 522 AN: 5176

South Asian (SAS) AF: 0.223 AC: 1075 AN: 4818

European-Finnish (FIN) AF: 0.232 AC: 2454 AN: 10566

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.278 AC: 18899 AN: 67952

Other (OTH) AF: 0.229 AC: 484 AN: 2116

Alfa AF: 0.190 Hom.: 620

Bravo AF: 0.211

Asia WGS AF: 0.155 AC: 541 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myopathy, congenital, with tremor Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lethal congenital contracture syndrome 4 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jul 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis, distal, type 1B Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.90
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: rs3835190; hg19: chr12-102046874;