rs2269529

Positions:

• chr22-36288308-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 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. 14/20 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 Likely 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:14
• Conservation: PhyloP100: 4.02

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH9. . Gene score misZ 3.473 (greater than the threshold 3.09). Trascript score misZ 6.1231 (greater than threshold 3.09). GenCC has associacion of gene with May-Hegglin anomaly, autosomal dominant nonsyndromic hearing loss, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, autosomal dominant nonsyndromic hearing loss 17.
• 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 id is 38967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36288308-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH9	NM_002473.6	c.4876A>G	p.Ile1626Val	missense_variant	34/41	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.4876A>G	p.Ile1626Val	missense_variant	34/41	1	NM_002473.6	ENSP00000216181.6
MYH9	ENST00000685801.1	c.4939A>G	p.Ile1647Val	missense_variant	35/42			ENSP00000510688.1
MYH9	ENST00000691109.1	n.5171A>G		non_coding_transcript_exon_variant	28/35

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

GnomAD3 exomes AF: 0.265 AC: 66555 AN: 251290 Hom.: 11216 AF XY: 0.274 AC XY: 37150 AN XY: 135830

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 SAS exome AF: 0.437

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

Gnomad4 AFR exome AF: 0.0674

Gnomad4 AMR exome AF: 0.281

Gnomad4 ASJ exome AF: 0.351

Gnomad4 EAS exome AF: 0.609

Gnomad4 SAS exome AF: 0.433

Gnomad4 FIN exome AF: 0.174

Gnomad4 NFE exome AF: 0.192

Gnomad4 OTH exome AF: 0.248

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

Gnomad4 AFR AF: 0.0719

Gnomad4 AMR AF: 0.249

Gnomad4 ASJ AF: 0.346

Gnomad4 EAS AF: 0.606

Gnomad4 SAS AF: 0.454

Gnomad4 FIN AF: 0.179

Gnomad4 NFE AF: 0.191

Gnomad4 OTH AF: 0.228

Alfa AF: 0.210 Hom.: 7204

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

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 38% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 35. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 12, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

Autosomal dominant nonsyndromic hearing loss 17 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal dominant nonsyndromic hearing loss 17;C5200934:Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 25, 2021

- -

Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

MYH9-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2269529; hg19: chr22-36684354; COSMIC: COSV53381533; COSMIC: COSV53381533;