rs138170393

Variant names:

• chr12-101626897-C-T
• rs138170393
• NM_002465.4:c.129C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-101626897-C-T
• chr12-101626897-C-A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_002465.4(MYBPC1):​c.129C>T​(p.Ser43Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000902 in 1,612,238 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (6 hom.)
• Consequence: MYBPC1 NM_002465.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.349
• 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: 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 12-101626897-C-T is Benign according to our data. Variant chr12-101626897-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211543.
• BP7: Synonymous conserved (PhyloP=-0.349 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00381 (580/152286) while in subpopulation AFR AF = 0.0133 (551/41556). AF 95% confidence interval is 0.0123. There are 7 homozygotes in GnomAd4. There are 267 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.129C>T	p.Ser43Ser	synonymous	Exon 4 of 32	NP_002456.2
	MYBPC1	NM_001404675.1		c.129C>T	p.Ser43Ser	synonymous	Exon 4 of 30	NP_001391604.1
	MYBPC1	NM_206819.4		c.129C>T	p.Ser43Ser	synonymous	Exon 4 of 31	NP_996555.1	Q00872-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC1	ENST00000361466.7	TSL:1 MANE Select	c.129C>T	p.Ser43Ser	synonymous	Exon 4 of 32	ENSP00000354849.2	Q00872-4
	MYBPC1	ENST00000361685.6	TSL:1	c.129C>T	p.Ser43Ser	synonymous	Exon 4 of 31	ENSP00000354845.2	Q00872-2
	MYBPC1	ENST00000551300.5	TSL:1	c.-244C>T		5_prime_UTR	Exon 5 of 32	ENSP00000447116.1	G3V1V7

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 581 AN: 152168 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00120 AC: 303 AN: 251470 AF XY: 0.00102

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000599 AC: 874 AN: 1459952 Hom.: 6 Cov.: 30 AF XY: 0.000636 AC XY: 462 AN XY: 726416

African (AFR) AF: 0.0149 AC: 499 AN: 33410

American (AMR) AF: 0.000648 AC: 29 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00168 AC: 145 AN: 86236

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53414

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.000131 AC: 145 AN: 1110244

Other (OTH) AF: 0.000862 AC: 52 AN: 60334

GnomAD4 genome AF: 0.00381 AC: 580 AN: 152286 Hom.: 7 Cov.: 32 AF XY: 0.00359 AC XY: 267 AN XY: 74472

African (AFR) AF: 0.0133 AC: 551 AN: 41556

American (AMR) AF: 0.000654 AC: 10 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68026

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.00447

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Arthrogryposis, distal, type 1B (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.1
DANN	Benign	0.74
PhyloP100		-0.35
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs138170393; hg19: chr12-102020675;