NM_002465.4:c.-93C>T

Variant names:

• chr12-101594978-C-T
• rs78173516
• NM_002465.4:c.-93C>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.-93C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,236,734 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (9 hom., cov: 32)
  • Exomes 𝑓: 0.010 (76 hom.)
• Consequence: MYBPC1 NM_002465.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.669
• Publications: 5 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=-0.49).
• BP6: Variant 12-101594978-C-T is Benign according to our data. Variant chr12-101594978-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 306703.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 = 0.00768 (1170/152264) while in subpopulation NFE AF = 0.0119 (806/68014). AF 95% confidence interval is 0.0112. There are 9 homozygotes in GnomAd4. There are 529 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.-93C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 32	NP_002456.2
	MYBPC1	NM_002465.4	MANE Select	c.-93C>T		5_prime_UTR	Exon 1 of 32	NP_002456.2
	MYBPC1	NM_001404675.1		c.-93C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 30	NP_001391604.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC1	ENST00000361466.7	TSL:1 MANE Select	c.-93C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 32	ENSP00000354849.2	Q00872-4
	MYBPC1	ENST00000361685.6	TSL:1	c.-93C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 31	ENSP00000354845.2	Q00872-2
	MYBPC1	ENST00000547405.5	TSL:1	c.-93C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 28	ENSP00000448175.1	Q00872-5

Frequencies

GnomAD3 genomes AF: 0.00769 AC: 1170 AN: 152146 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00956

GnomAD4 exome AF: 0.0105 AC: 11377 AN: 1084470 Hom.: 76 Cov.: 14 AF XY: 0.0100 AC XY: 5563 AN XY: 554326

African (AFR) AF: 0.00187 AC: 48 AN: 25652

American (AMR) AF: 0.00421 AC: 170 AN: 40368

Ashkenazi Jewish (ASJ) AF: 0.0345 AC: 788 AN: 22830

East Asian (EAS) AF: 0.000398 AC: 15 AN: 37678

South Asian (SAS) AF: 0.000690 AC: 51 AN: 73900

European-Finnish (FIN) AF: 0.00183 AC: 93 AN: 50710

Middle Eastern (MID) AF: 0.000399 AC: 2 AN: 5010

European-Non Finnish (NFE) AF: 0.0124 AC: 9658 AN: 780780

Other (OTH) AF: 0.0116 AC: 552 AN: 47542

GnomAD4 genome AF: 0.00768 AC: 1170 AN: 152264 Hom.: 9 Cov.: 32 AF XY: 0.00710 AC XY: 529 AN XY: 74458

African (AFR) AF: 0.00265 AC: 110 AN: 41560

American (AMR) AF: 0.00563 AC: 86 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0383 AC: 133 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0119 AC: 806 AN: 68014

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00164 Hom.: 0

Bravo AF: 0.00760

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.0
DANN	Benign	0.82
PhyloP100		0.67
PromoterAI		-0.044	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs78173516; hg19: chr12-101988756;