NM_002474.3:c.2061C>T

Variant names:

• chr16-15748166-G-A
• rs880071
• NM_002474.3:c.2061C>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_002474.3(MYH11):​c.2061C>T​(p.Ser687Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0674 in 1,613,574 control chromosomes in the GnomAD database, including 4,133 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S687S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.063 (335 hom., cov: 32)
  • Exomes 𝑓: 0.068 (3798 hom.)
• Consequence: MYH11 NM_002474.3 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -3.89
• Publications: 14 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, Unknown 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
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• visceral myopathy 2

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 16-15748166-G-A is Benign according to our data. Variant chr16-15748166-G-A is described in ClinVar as Benign. ClinVar VariationId is 138328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002474.3. 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
	MYH11	NM_002474.3	MANE Select	c.2061C>T	p.Ser687Ser	splice_region synonymous	Exon 17 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.2082C>T	p.Ser694Ser	splice_region synonymous	Exon 18 of 43	NP_001035202.1	P35749-3
	MYH11	NM_001040114.2		c.2082C>T	p.Ser694Ser	splice_region synonymous	Exon 18 of 42	NP_001035203.1	P35749-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.2061C>T	p.Ser687Ser	splice_region synonymous	Exon 17 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.2082C>T	p.Ser694Ser	splice_region synonymous	Exon 18 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.2082C>T	p.Ser694Ser	splice_region synonymous	Exon 18 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.0630 AC: 9583 AN: 152160 Hom.: 337 Cov.: 32

Gnomad AFR AF: 0.0542

Gnomad AMI AF: 0.0341

Gnomad AMR AF: 0.0461

Gnomad ASJ AF: 0.0853

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.0706

Gnomad FIN AF: 0.0281

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0677

Gnomad OTH AF: 0.0692

GnomAD2 exomes AF: 0.0649 AC: 16247 AN: 250184 AF XY: 0.0660

Gnomad AFR exome AF: 0.0512

Gnomad AMR exome AF: 0.0277

Gnomad ASJ exome AF: 0.0902

Gnomad EAS exome AF: 0.185

Gnomad FIN exome AF: 0.0296

Gnomad NFE exome AF: 0.0634

Gnomad OTH exome AF: 0.0644

GnomAD4 exome AF: 0.0678 AC: 99136 AN: 1461296 Hom.: 3798 Cov.: 34 AF XY: 0.0680 AC XY: 49460 AN XY: 726944

African (AFR) AF: 0.0528 AC: 1766 AN: 33478

American (AMR) AF: 0.0304 AC: 1358 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0894 AC: 2336 AN: 26136

East Asian (EAS) AF: 0.152 AC: 6045 AN: 39696

South Asian (SAS) AF: 0.0646 AC: 5568 AN: 86258

European-Finnish (FIN) AF: 0.0307 AC: 1623 AN: 52842

Middle Eastern (MID) AF: 0.0654 AC: 377 AN: 5768

European-Non Finnish (NFE) AF: 0.0677 AC: 75337 AN: 1112002

Other (OTH) AF: 0.0783 AC: 4726 AN: 60394

GnomAD4 genome AF: 0.0630 AC: 9586 AN: 152278 Hom.: 335 Cov.: 32 AF XY: 0.0606 AC XY: 4513 AN XY: 74462

African (AFR) AF: 0.0542 AC: 2254 AN: 41560

American (AMR) AF: 0.0460 AC: 704 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0853 AC: 296 AN: 3472

East Asian (EAS) AF: 0.173 AC: 897 AN: 5172

South Asian (SAS) AF: 0.0702 AC: 339 AN: 4826

European-Finnish (FIN) AF: 0.0281 AC: 299 AN: 10622

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0676 AC: 4600 AN: 68012

Other (OTH) AF: 0.0681 AC: 144 AN: 2116

Alfa AF: 0.0659 Hom.: 243

Bravo AF: 0.0638

Asia WGS AF: 0.117 AC: 407 AN: 3478

EpiCase AF: 0.0677

EpiControl AF: 0.0616

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Aortic aneurysm, familial thoracic 4 (3)
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 (1)
-	-	1	Visceral myopathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.0040
DANN	Benign	0.46
PhyloP100		-3.9
Mutation Taster		=98/2	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: rs880071; hg19: chr16-15842023; COSMIC: COSV55545525; COSMIC: COSV55545525;