chr22-36304129-A-G

Variant names:

• chr22-36304129-A-G
• rs9619601
• NM_002473.6:c.2256T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002473.6(MYH9):​c.2256T>C​(p.Asn752Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0528 in 1,613,526 control chromosomes in the GnomAD database, including 2,449 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (177 hom., cov: 33)
  • Exomes 𝑓: 0.053 (2272 hom.)
• Consequence: MYH9 NM_002473.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.14
• Publications: 16 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 22-36304129-A-G is Benign according to our data. Variant chr22-36304129-A-G is described in ClinVar as [Benign]. Clinvar id is 44555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.089 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.2256T>C	p.Asn752Asn	synonymous_variant	Exon 19 of 41	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.2256T>C	p.Asn752Asn	synonymous_variant	Exon 19 of 41	1	NM_002473.6	ENSP00000216181.6
MYH9	ENST00000685801.1	c.2319T>C	p.Asn773Asn	synonymous_variant	Exon 20 of 42			ENSP00000510688.1
MYH9	ENST00000691109.1	n.2551T>C		non_coding_transcript_exon_variant	Exon 13 of 35
MYH9	ENST00000473022.1	n.-104T>C		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0479 AC: 7285 AN: 152134 Hom.: 178 Cov.: 33

Gnomad AFR AF: 0.0384

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.0536

Gnomad EAS AF: 0.0961

Gnomad SAS AF: 0.0691

Gnomad FIN AF: 0.0626

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0520

Gnomad OTH AF: 0.0468

GnomAD2 exomes AF: 0.0533 AC: 13400 AN: 251216 AF XY: 0.0549

Gnomad AFR exome AF: 0.0399

Gnomad AMR exome AF: 0.0197

Gnomad ASJ exome AF: 0.0513

Gnomad EAS exome AF: 0.109

Gnomad FIN exome AF: 0.0658

Gnomad NFE exome AF: 0.0521

Gnomad OTH exome AF: 0.0451

GnomAD4 exome AF: 0.0533 AC: 77951 AN: 1461274 Hom.: 2272 Cov.: 32 AF XY: 0.0536 AC XY: 38974 AN XY: 726928

African (AFR) AF: 0.0367 AC: 1230 AN: 33478

American (AMR) AF: 0.0197 AC: 883 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0533 AC: 1392 AN: 26136

East Asian (EAS) AF: 0.0990 AC: 3930 AN: 39700

South Asian (SAS) AF: 0.0628 AC: 5417 AN: 86256

European-Finnish (FIN) AF: 0.0655 AC: 3460 AN: 52832

Middle Eastern (MID) AF: 0.0413 AC: 238 AN: 5768

European-Non Finnish (NFE) AF: 0.0524 AC: 58225 AN: 1111994

Other (OTH) AF: 0.0526 AC: 3176 AN: 60386

GnomAD4 genome AF: 0.0478 AC: 7282 AN: 152252 Hom.: 177 Cov.: 33 AF XY: 0.0477 AC XY: 3553 AN XY: 74452

African (AFR) AF: 0.0383 AC: 1591 AN: 41560

American (AMR) AF: 0.0221 AC: 338 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0536 AC: 186 AN: 3470

East Asian (EAS) AF: 0.0960 AC: 496 AN: 5168

South Asian (SAS) AF: 0.0684 AC: 329 AN: 4812

European-Finnish (FIN) AF: 0.0626 AC: 665 AN: 10616

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0520 AC: 3539 AN: 68012

Other (OTH) AF: 0.0478 AC: 101 AN: 2114

Alfa AF: 0.0479 Hom.: 288

Bravo AF: 0.0439

Asia WGS AF: 0.0930 AC: 323 AN: 3478

EpiCase AF: 0.0483

EpiControl AF: 0.0494

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Asn752Asn in Exon 19 of MYH9: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 4.6% (322/7020) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs9619601). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 03, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal dominant nonsyndromic hearing loss 17 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

MYH9-related disorder Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.3
DANN	Benign	0.82
PhyloP100		3.1
Mutation Taster		=96/4	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: rs9619601; hg19: chr22-36700175; COSMIC: COSV53386660; COSMIC: COSV53386660;