rs9619601

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:9
• 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: 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 -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 VariationId 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.

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.2256T>C	p.Asn752Asn	synonymous	Exon 19 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.2256T>C	p.Asn752Asn	synonymous	Exon 19 of 41	ENSP00000216181.6	P35579-1
	MYH9	ENST00000685801.1		c.2319T>C	p.Asn773Asn	synonymous	Exon 20 of 42	ENSP00000510688.1	A0A8I5KWT8
	MYH9	ENST00000955568.1		c.2319T>C	p.Asn773Asn	synonymous	Exon 20 of 42	ENSP00000625627.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 17 (1)
-	-	1	MYH9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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;