rs2272556

Variant names:

• chr16-15735679-G-C
• rs2272556
• NM_002474.3:c.3294-101C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002474.3(MYH11):​c.3294-101C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,139,660 control chromosomes in the GnomAD database, including 545 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (75 hom., cov: 32)
  • Exomes 𝑓: 0.016 (470 hom.)
• Consequence: MYH11 NM_002474.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.13
• Publications: 2 publications found

Genes affected

MYH11 (HGNC:7569): (myosin heavy chain 11) The protein encoded by this gene is a smooth muscle myosin belonging to the myosin heavy chain family. The gene product is a subunit of a hexameric protein that consists of two heavy chain subunits and two pairs of non-identical light chain subunits. It functions as a major contractile protein, converting chemical energy into mechanical energy through the hydrolysis of ATP. A chromosomal rearrangement involving this gene is associated with acute myeloid leukemia of the M4Eo subtype. Mutations in this gene are associated with visceral myopathy, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, and familial thoracic aortic aneurysm 4. [provided by RefSeq, May 2022]

MYH11 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• aortic aneurysm, familial thoracic 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• megacystis-microcolon-intestinal hypoperistalsis syndrome 2

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• megacystis-microcolon-intestinal hypoperistalsis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• visceral myopathy 2

  Inheritance: AR, AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 16-15735679-G-C is Benign according to our data. Variant chr16-15735679-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 674681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.3294-101C>G		intron_variant	Intron 25 of 40	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.3315-101C>G		intron_variant	Intron 26 of 42	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.3315-101C>G		intron_variant	Intron 26 of 41		NP_001035203.1
MYH11	NM_022844.3	c.3294-101C>G		intron_variant	Intron 25 of 41		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.3294-101C>G		intron_variant	Intron 25 of 40	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.3315-101C>G		intron_variant	Intron 26 of 42	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2185 AN: 152222 Hom.: 77 Cov.: 32

Gnomad AFR AF: 0.00383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.0460

Gnomad FIN AF: 0.0151

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00895

Gnomad OTH AF: 0.0181

GnomAD4 exome AF: 0.0155 AC: 15326 AN: 987320 Hom.: 470 AF XY: 0.0164 AC XY: 8379 AN XY: 509576

African (AFR) AF: 0.00245 AC: 59 AN: 24096

American (AMR) AF: 0.00508 AC: 202 AN: 39748

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 417 AN: 22936

East Asian (EAS) AF: 0.127 AC: 4637 AN: 36430

South Asian (SAS) AF: 0.0378 AC: 2837 AN: 74954

European-Finnish (FIN) AF: 0.0137 AC: 634 AN: 46326

Middle Eastern (MID) AF: 0.00896 AC: 42 AN: 4686

European-Non Finnish (NFE) AF: 0.00815 AC: 5651 AN: 693314

Other (OTH) AF: 0.0189 AC: 847 AN: 44830

GnomAD4 genome AF: 0.0143 AC: 2181 AN: 152340 Hom.: 75 Cov.: 32 AF XY: 0.0154 AC XY: 1148 AN XY: 74486

African (AFR) AF: 0.00382 AC: 159 AN: 41584

American (AMR) AF: 0.00791 AC: 121 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3470

East Asian (EAS) AF: 0.155 AC: 801 AN: 5178

South Asian (SAS) AF: 0.0456 AC: 220 AN: 4826

European-Finnish (FIN) AF: 0.0151 AC: 160 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00895 AC: 609 AN: 68044

Other (OTH) AF: 0.0175 AC: 37 AN: 2116

Alfa AF: 0.00836 Hom.: 2

Bravo AF: 0.0128

Asia WGS AF: 0.0930 AC: 323 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 16, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.022
DANN	Benign	0.64
PhyloP100		-1.1
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: rs2272556; hg19: chr16-15829536; COSMIC: COSV55552625; COSMIC: COSV55552625;