rs11570097

Variant names:

• chr11-47337392-G-A
• rs11570097
• NM_000256.3:c.2601C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-47337392-G-A
• chr11-47337392-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000256.3(MYBPC3):​c.2601C>T​(p.Ile867Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,582,200 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (52 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (31 hom.)
• Consequence: MYBPC3 NM_000256.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.001613
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.637
• Publications: 4 publications found

Genes affected

MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

MYBPC3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AR, AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 11-47337392-G-A is Benign according to our data. Variant chr11-47337392-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.637 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0132 (2006/152300) while in subpopulation AFR AF = 0.046 (1911/41548). AF 95% confidence interval is 0.0443. There are 52 homozygotes in GnomAd4. There are 957 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 52 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000256.3. 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
	MYBPC3	NM_000256.3	MANE Select	c.2601C>T	p.Ile867Ile	splice_region synonymous	Exon 25 of 35	NP_000247.2	Q14896-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.2601C>T	p.Ile867Ile	splice_region synonymous	Exon 25 of 35	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.2601C>T	p.Ile867Ile	splice_region synonymous	Exon 24 of 34	ENSP00000382193.2	A8MXZ9
	MYBPC3	ENST00000544791.1	TSL:5	n.*106C>T		splice_region non_coding_transcript_exon	Exon 25 of 27	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1998 AN: 152182 Hom.: 51 Cov.: 31

Gnomad AFR AF: 0.0459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00370 AC: 849 AN: 229402 AF XY: 0.00260

Gnomad AFR exome AF: 0.0478

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000772

Gnomad OTH exome AF: 0.00142

GnomAD4 exome AF: 0.00133 AC: 1897 AN: 1429900 Hom.: 31 Cov.: 33 AF XY: 0.00112 AC XY: 790 AN XY: 706988

African (AFR) AF: 0.0452 AC: 1498 AN: 33130

American (AMR) AF: 0.00324 AC: 142 AN: 43812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24838

East Asian (EAS) AF: 0.00 AC: 0 AN: 39236

South Asian (SAS) AF: 0.000119 AC: 10 AN: 83828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45880

Middle Eastern (MID) AF: 0.00411 AC: 23 AN: 5602

European-Non Finnish (NFE) AF: 0.0000384 AC: 42 AN: 1094444

Other (OTH) AF: 0.00308 AC: 182 AN: 59130

GnomAD4 genome AF: 0.0132 AC: 2006 AN: 152300 Hom.: 52 Cov.: 31 AF XY: 0.0129 AC XY: 957 AN XY: 74470

African (AFR) AF: 0.0460 AC: 1911 AN: 41548

American (AMR) AF: 0.00457 AC: 70 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00492 Hom.: 18

Bravo AF: 0.0149

Asia WGS AF: 0.00173 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	Hypertrophic cardiomyopathy 4 (4)
-	-	4	not specified (4)
-	-	2	Hypertrophic cardiomyopathy (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Left ventricular noncompaction 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.029
DANN	Benign	0.92
PhyloP100		-0.64
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0016
dbscSNV1_RF	Benign	0.076
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: rs11570097; hg19: chr11-47358943;