12-101651253-A-T

Variant names:

• chr12-101651253-A-T
• rs825045
• NM_002465.4:c.1386A>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001404675.1(MYBPC1):​c.1386A>T​(p.Thr462Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0578 in 1,613,834 control chromosomes in the GnomAD database, including 3,420 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (822 hom., cov: 32)
  • Exomes 𝑓: 0.055 (2598 hom.)
• Consequence: MYBPC1 NM_001404675.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.340
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 12-101651253-A-T is Benign according to our data. Variant chr12-101651253-A-T is described in ClinVar as Benign. ClinVar VariationId is 129641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001404675.1. 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.1386A>T	p.Thr462Thr	synonymous	Exon 16 of 32	NP_002456.2
	MYBPC1	NM_001404675.1		c.1386A>T	p.Thr462Thr	synonymous	Exon 16 of 30	NP_001391604.1
	MYBPC1	NM_001254718.3		c.1311A>T	p.Thr437Thr	synonymous	Exon 14 of 30	NP_001241647.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC1	ENST00000361466.7	TSL:1 MANE Select	c.1386A>T	p.Thr462Thr	synonymous	Exon 16 of 32	ENSP00000354849.2
	MYBPC1	ENST00000361685.6	TSL:1	c.1386A>T	p.Thr462Thr	synonymous	Exon 16 of 31	ENSP00000354845.2
	MYBPC1	ENST00000545503.6	TSL:1	c.1311A>T	p.Thr437Thr	synonymous	Exon 14 of 30	ENSP00000440034.2

Frequencies

GnomAD3 genomes AF: 0.0861 AC: 13081 AN: 151972 Hom.: 823 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.0495

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.0477

Gnomad FIN AF: 0.0461

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0547

Gnomad OTH AF: 0.0758

GnomAD2 exomes AF: 0.0541 AC: 13616 AN: 251460 AF XY: 0.0529

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.0330

Gnomad ASJ exome AF: 0.0267

Gnomad EAS exome AF: 0.00484

Gnomad FIN exome AF: 0.0445

Gnomad NFE exome AF: 0.0570

Gnomad OTH exome AF: 0.0534

GnomAD4 exome AF: 0.0548 AC: 80128 AN: 1461744 Hom.: 2598 Cov.: 32 AF XY: 0.0545 AC XY: 39600 AN XY: 727188

African (AFR) AF: 0.178 AC: 5971 AN: 33470

American (AMR) AF: 0.0354 AC: 1583 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 760 AN: 26132

East Asian (EAS) AF: 0.00264 AC: 105 AN: 39698

South Asian (SAS) AF: 0.0475 AC: 4095 AN: 86256

European-Finnish (FIN) AF: 0.0471 AC: 2518 AN: 53418

Middle Eastern (MID) AF: 0.0439 AC: 253 AN: 5768

European-Non Finnish (NFE) AF: 0.0554 AC: 61634 AN: 1111892

Other (OTH) AF: 0.0531 AC: 3209 AN: 60392

GnomAD4 genome AF: 0.0861 AC: 13093 AN: 152090 Hom.: 822 Cov.: 32 AF XY: 0.0833 AC XY: 6194 AN XY: 74348

African (AFR) AF: 0.180 AC: 7443 AN: 41460

American (AMR) AF: 0.0494 AC: 754 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3472

East Asian (EAS) AF: 0.00405 AC: 21 AN: 5180

South Asian (SAS) AF: 0.0477 AC: 230 AN: 4820

European-Finnish (FIN) AF: 0.0461 AC: 487 AN: 10570

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0548 AC: 3724 AN: 68006

Other (OTH) AF: 0.0750 AC: 158 AN: 2106

Alfa AF: 0.0582 Hom.: 120

Bravo AF: 0.0895

Asia WGS AF: 0.0330 AC: 113 AN: 3478

EpiCase AF: 0.0516

EpiControl AF: 0.0535

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Arthrogryposis, distal, type 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	3.2
DANN	Benign	0.71
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs825045; hg19: chr12-102045031;