NM_002474.3:c.4396_4398delAAAinsCAG

Variant names:

• chr16-15721602-TTT-CTG
• NM_002474.3:c.4396_4398delAAAinsCAG
• MYH11 p.Lys1466Gln

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_002474.3(MYH11):c.4396_4398delAAAinsCAG (p.Lys1466Gln) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.K1466Q: Uncertain_significance (ClinVar VariationId 375854, 2 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.21
• Publications: 0 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: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• aortic aneurysm, familial thoracic 4

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

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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: AR, AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

NDE1 (HGNC:17619): (nudE neurodevelopment protein 1) This gene encodes a member of the nuclear distribution E (NudE) family of proteins. The encoded protein is localized at the centrosome and interacts with other centrosome components as part of a multiprotein complex that regulates dynein function. This protein plays an essential role in microtubule organization, mitosis and neuronal migration. Mutations in this gene cause lissencephaly 4, a disorder characterized by lissencephaly, severe brain atrophy, microcephaly, and severe cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

NDE1 Gene-Disease associations (from GenCC):

• lissencephaly 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• microcephaly with lissencephaly and/or hydranencephaly

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• hydranencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• microlissencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• NDE1-related microhydranencephaly

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002474.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MYH11 NM_002474.3	MANE Select	c.4396_4398delAAAinsCAG p.Lys1466Gln	missense	N/A	Prot: NP_002465.1 UniProt:
	MYH11 NM_001040113.2	MANE Plus Clinical	c.4417_4419delAAAinsCAG p.Lys1473Gln	missense	N/A	Prot: NP_001035202.1 UniProt:
	NDE1 NM_017668.3	MANE Select	c.948-2589_948-2587delTTTinsCTG	intron	Intron 8 of 8	Prot: NP_060138.1 UniProt:

MYH11 NM_002474.3

MANE Select

HGVSc / HGVSpc.4396_4398delAAAinsCAGp.Lys1466Gln

Exon rankN/A

missense

Prot: NP_002465.1UniProt: A0A024QZJ4P35749-1

MYH11 NM_001040113.2

MANE Plus Clinical

HGVSc / HGVSpc.4417_4419delAAAinsCAGp.Lys1473Gln

Exon rankN/A

missense

Prot: NP_001035202.1UniProt: P35749-3

NDE1 NM_017668.3

MANE Select

HGVSc / HGVSpc.948-2589_948-2587delTTTinsCTG

Exon rankIntron 8 of 8

intron

Prot: NP_060138.1UniProt: Q9NXR1-2X5DR54

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MYH11 ENST00000300036.6	TSL:1MANE Select	c.4396_4398delAAAinsCAG p.Lys1466Gln	missense	N/A	Prot: ENSP00000300036.5 UniProt:
	MYH11 ENST00000452625.7	TSL:1MANE Plus Clinical	c.4417_4419delAAAinsCAG p.Lys1473Gln	missense	N/A	Prot: ENSP00000407821.2 UniProt:
	MYH11 ENST00000396324.7	TSL:1	c.4417_4419delAAAinsCAG p.Lys1473Gln	missense	N/A	Prot: ENSP00000379616.3 UniProt:

MYH11 ENST00000300036.6

TSL:1MANE Select

HGVSc / HGVSpc.4396_4398delAAAinsCAGp.Lys1466Gln

Exon rankN/A

missense

Prot: ENSP00000300036.5UniProt: P35749-1

MYH11 ENST00000452625.7

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.4417_4419delAAAinsCAGp.Lys1473Gln

Exon rankN/A

missense

Prot: ENSP00000407821.2UniProt: P35749-3

MYH11 ENST00000396324.7

TSL:1

HGVSc / HGVSpc.4417_4419delAAAinsCAGp.Lys1473Gln

Exon rankN/A

missense

Prot: ENSP00000379616.3UniProt: P35749-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	4.2

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr16-15815459;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar