chr22-36299030-G-C

Variant names:

• chr22-36299030-G-C
• rs757028068
• NM_002473.6:c.2989C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000216181.11(MYH9):​c.2989C>G​(p.Leu997Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L997L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYH9 ENST00000216181.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.526
• Publications: 0 publications found

Genes affected

MYH9 (HGNC:7579): (myosin heavy chain 9) This gene encodes a conventional non-muscle myosin; this protein should not be confused with the unconventional myosin-9a or 9b (MYO9A or MYO9B). The encoded protein is a myosin IIA heavy chain that contains an IQ domain and a myosin head-like domain which is involved in several important functions, including cytokinesis, cell motility and maintenance of cell shape. Defects in this gene have been associated with non-syndromic sensorineural deafness autosomal dominant type 17, Epstein syndrome, Alport syndrome with macrothrombocytopenia, Sebastian syndrome, Fechtner syndrome and macrothrombocytopenia with progressive sensorineural deafness. [provided by RefSeq, Dec 2011]

MYH9 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 17

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• May-Hegglin anomaly

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37732473).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000216181.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	NM_002473.6	MANE Select	c.2989C>G	p.Leu997Val	missense	Exon 24 of 41	NP_002464.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	ENST00000216181.11	TSL:1 MANE Select	c.2989C>G	p.Leu997Val	missense	Exon 24 of 41	ENSP00000216181.6
	MYH9	ENST00000685801.1		c.3052C>G	p.Leu1018Val	missense	Exon 25 of 42	ENSP00000510688.1
	MYH9	ENST00000691109.1		n.3284C>G		non_coding_transcript_exon	Exon 18 of 35

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461796 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727214

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	0.022
Eigen_PC	Benign	0.060
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.53
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.017	D
Polyphen		0.32	B
Vest4		0.49
MutPred		0.23		Loss of ubiquitination at K992 (P = 0.1651)
MVP		0.87
MPC		0.75
ClinPred		0.77	D
GERP RS		2.2
Varity_R		0.10
gMVP		0.31
Mutation Taster		=88/12	polymorphism

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: rs757028068; hg19: chr22-36695076;