rs2269529

Variant names:

• chr22-36288308-T-C
• rs2269529
• NM_002473.6:c.4876A>G

Variant summary

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

The NM_002473.6(MYH9):​c.4876A>G​(p.Ile1626Val) variant causes a missense change. The variant allele was found at a frequency of 0.219 in 1,613,510 control chromosomes in the GnomAD database, including 47,050 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I1626I) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.19 (3716 hom., cov: 32)
  • Exomes 𝑓: 0.22 (43334 hom.)
• Consequence: MYH9 NM_002473.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 4.02
• Publications: 60 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: Labcorp Genetics (formerly Invitae), G2P
• macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.1029584E-5).
• BP6: Variant 22-36288308-T-C is Benign according to our data. Variant chr22-36288308-T-C is described in ClinVar as Benign. ClinVar VariationId is 38967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002473.6. 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
	MYH9	NM_002473.6	MANE Select	c.4876A>G	p.Ile1626Val	missense	Exon 34 of 41	NP_002464.1	P35579-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	ENST00000216181.11	TSL:1 MANE Select	c.4876A>G	p.Ile1626Val	missense	Exon 34 of 41	ENSP00000216181.6	P35579-1
	MYH9	ENST00000685801.1		c.4939A>G	p.Ile1647Val	missense	Exon 35 of 42	ENSP00000510688.1	A0A8I5KWT8
	MYH9	ENST00000955568.1		c.4939A>G	p.Ile1647Val	missense	Exon 35 of 42	ENSP00000625627.1

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28802 AN: 151840 Hom.: 3702 Cov.: 32

Gnomad AFR AF: 0.0718

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.222

GnomAD2 exomes AF: 0.265 AC: 66555 AN: 251290 AF XY: 0.274

Gnomad AFR exome AF: 0.0697

Gnomad AMR exome AF: 0.286

Gnomad ASJ exome AF: 0.351

Gnomad EAS exome AF: 0.611

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.194

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.222 AC: 324972 AN: 1461550 Hom.: 43334 Cov.: 41 AF XY: 0.229 AC XY: 166794 AN XY: 727090

African (AFR) AF: 0.0674 AC: 2257 AN: 33478

American (AMR) AF: 0.281 AC: 12587 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 9168 AN: 26134

East Asian (EAS) AF: 0.609 AC: 24172 AN: 39696

South Asian (SAS) AF: 0.433 AC: 37373 AN: 86252

European-Finnish (FIN) AF: 0.174 AC: 9287 AN: 53260

Middle Eastern (MID) AF: 0.266 AC: 1535 AN: 5768

European-Non Finnish (NFE) AF: 0.192 AC: 213629 AN: 1111862

Other (OTH) AF: 0.248 AC: 14964 AN: 60382

GnomAD4 genome AF: 0.190 AC: 28843 AN: 151960 Hom.: 3716 Cov.: 32 AF XY: 0.198 AC XY: 14710 AN XY: 74250

African (AFR) AF: 0.0719 AC: 2982 AN: 41500

American (AMR) AF: 0.249 AC: 3799 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 1197 AN: 3460

East Asian (EAS) AF: 0.606 AC: 3100 AN: 5114

South Asian (SAS) AF: 0.454 AC: 2177 AN: 4798

European-Finnish (FIN) AF: 0.179 AC: 1891 AN: 10564

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 12973 AN: 67938

Other (OTH) AF: 0.228 AC: 482 AN: 2112

Alfa AF: 0.211 Hom.: 9787

Bravo AF: 0.190

TwinsUK AF: 0.190 AC: 706

ALSPAC AF: 0.193 AC: 744

ESP6500AA AF: 0.0724 AC: 319

ESP6500EA AF: 0.198 AC: 1704

ExAC AF: 0.258 AC: 31375

Asia WGS AF: 0.525 AC: 1826 AN: 3478

EpiCase AF: 0.209

EpiControl AF: 0.209

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	2	Autosomal dominant nonsyndromic hearing loss 17 (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 17;C5200934:Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss (1)
-	-	1	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss (1)
-	-	1	MYH9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Benign	0.72
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.000031	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.0
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.22
Sift	Benign	0.33	T
Sift4G	Benign	0.16	T
Polyphen		0.042	B
Vest4		0.057
MPC		0.42
ClinPred		0.0072	T
GERP RS		4.5
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.076
gMVP		0.11
Mutation Taster		=93/7	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: rs2269529; hg19: chr22-36684354; COSMIC: COSV53381533; COSMIC: COSV53381533;