rs56063322

Variant names:

• chr22-36295107-C-G
• rs56063322
• NM_002473.6:c.3486-31G>C

Your query was ambiguous. Multiple possible variants found:

• chr22-36295107-C-G
• chr22-36295107-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002473.6(MYH9):​c.3486-31G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00549 in 1,613,990 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (36 hom.)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0820
• Publications: 2 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=-0.8).
• BP6: Variant 22-36295107-C-G is Benign according to our data. Variant chr22-36295107-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 258742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00493 (751/152296) while in subpopulation NFE AF = 0.00578 (393/68024). AF 95% confidence interval is 0.00531. There are 5 homozygotes in GnomAd4. There are 447 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 751 AD gene.

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.3486-31G>C		intron	N/A	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.3486-31G>C		intron	N/A	ENSP00000216181.6	P35579-1
	MYH9	ENST00000859030.1		c.3494G>C	p.Gly1165Ala	missense	Exon 27 of 41	ENSP00000529089.1
	MYH9	ENST00000685801.1		c.3549-31G>C		intron	N/A	ENSP00000510688.1	A0A8I5KWT8

Frequencies

GnomAD3 genomes AF: 0.00493 AC: 750 AN: 152178 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00578

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00560 AC: 1407 AN: 251262 AF XY: 0.00574

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0269

Gnomad NFE exome AF: 0.00598

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00554 AC: 8103 AN: 1461694 Hom.: 36 Cov.: 32 AF XY: 0.00558 AC XY: 4055 AN XY: 727168

African (AFR) AF: 0.000478 AC: 16 AN: 33478

American (AMR) AF: 0.000626 AC: 28 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00130 AC: 34 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00236 AC: 204 AN: 86258

European-Finnish (FIN) AF: 0.0264 AC: 1406 AN: 53260

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00552 AC: 6139 AN: 1111978

Other (OTH) AF: 0.00447 AC: 270 AN: 60394

GnomAD4 genome AF: 0.00493 AC: 751 AN: 152296 Hom.: 5 Cov.: 33 AF XY: 0.00600 AC XY: 447 AN XY: 74472

African (AFR) AF: 0.000602 AC: 25 AN: 41562

American (AMR) AF: 0.000719 AC: 11 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.0283 AC: 301 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00578 AC: 393 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00434 Hom.: 0

Bravo AF: 0.00270

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.3
DANN	Benign	0.60
PhyloP100		-0.082
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs56063322; hg19: chr22-36691153;