rs2269530

Variant names:

• chr22-36288312-C-A
• rs2269530
• NM_002473.6:c.4872G>T

Your query was ambiguous. Multiple possible variants found:

• chr22-36288312-C-A
• chr22-36288312-C-T
• chr22-36288312-C-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.4872G>T​(p.Ala1624Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,613,466 control chromosomes in the GnomAD database, including 46,971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1624A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.19 (3705 hom., cov: 32)
  • Exomes 𝑓: 0.22 (43266 hom.)
• Consequence: MYH9 NM_002473.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.15
• Publications: 28 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 (BayesDel_noAF=-0.51).
• BP6: Variant 22-36288312-C-A is Benign according to our data. Variant chr22-36288312-C-A is described in ClinVar as Benign. ClinVar VariationId is 44565.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.4872G>T	p.Ala1624Ala	synonymous	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.4872G>T	p.Ala1624Ala	synonymous	Exon 34 of 41	ENSP00000216181.6	P35579-1
	MYH9	ENST00000685801.1		c.4935G>T	p.Ala1645Ala	synonymous	Exon 35 of 42	ENSP00000510688.1	A0A8I5KWT8
	MYH9	ENST00000955568.1		c.4935G>T	p.Ala1645Ala	synonymous	Exon 35 of 42	ENSP00000625627.1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28749 AN: 151830 Hom.: 3692 Cov.: 32

Gnomad AFR AF: 0.0709

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.221

GnomAD2 exomes AF: 0.265 AC: 66508 AN: 251282 AF XY: 0.273

Gnomad AFR exome AF: 0.0689

Gnomad AMR exome AF: 0.285

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: 324675 AN: 1461516 Hom.: 43266 Cov.: 40 AF XY: 0.229 AC XY: 166628 AN XY: 727072

African (AFR) AF: 0.0659 AC: 2207 AN: 33478

American (AMR) AF: 0.281 AC: 12587 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 9167 AN: 26132

East Asian (EAS) AF: 0.609 AC: 24168 AN: 39694

South Asian (SAS) AF: 0.433 AC: 37356 AN: 86250

European-Finnish (FIN) AF: 0.174 AC: 9286 AN: 53262

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

European-Non Finnish (NFE) AF: 0.192 AC: 213429 AN: 1111830

Other (OTH) AF: 0.247 AC: 14940 AN: 60380

GnomAD4 genome AF: 0.189 AC: 28789 AN: 151950 Hom.: 3705 Cov.: 32 AF XY: 0.198 AC XY: 14685 AN XY: 74242

African (AFR) AF: 0.0710 AC: 2946 AN: 41492

American (AMR) AF: 0.249 AC: 3798 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 1197 AN: 3464

East Asian (EAS) AF: 0.606 AC: 3098 AN: 5114

South Asian (SAS) AF: 0.453 AC: 2176 AN: 4800

European-Finnish (FIN) AF: 0.179 AC: 1890 AN: 10568

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 12963 AN: 67926

Other (OTH) AF: 0.227 AC: 480 AN: 2112

Alfa AF: 0.198 Hom.: 2768

Bravo AF: 0.189

Asia WGS AF: 0.525 AC: 1824 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
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Autosomal dominant nonsyndromic hearing loss 17 (2)
-	-	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
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.27
DANN	Benign	0.52
PhyloP100		-1.1
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	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: rs2269530; hg19: chr22-36684358; COSMIC: COSV53381543;