rs56200894

Variant names:

• chr22-36349230-G-C
• rs56200894
• NM_002473.6:c.7C>G

Your query was ambiguous. Multiple possible variants found:

• chr22-36349230-G-C
• chr22-36349230-G-T

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.7C>G​(p.Gln3Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00246 in 1,614,070 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (6 hom.)
• Consequence: MYH9 NM_002473.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:12
• Conservation: PhyloP100: 5.18
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011276066).
• BP6: Variant 22-36349230-G-C is Benign according to our data. Variant chr22-36349230-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0022 (335/152308) while in subpopulation AMR AF = 0.0051 (78/15300). AF 95% confidence interval is 0.00419. There are 1 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 335 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.7C>G	p.Gln3Glu	missense	Exon 2 of 41	NP_002464.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	ENST00000216181.11	TSL:1 MANE Select	c.7C>G	p.Gln3Glu	missense	Exon 2 of 41	ENSP00000216181.6
	MYH9	ENST00000401701.1	TSL:1	c.7C>G	p.Gln3Glu	missense	Exon 2 of 6	ENSP00000384631.1
	MYH9	ENST00000685801.1		c.7C>G	p.Gln3Glu	missense	Exon 2 of 42	ENSP00000510688.1

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 335 AN: 152190 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00161 AC: 399 AN: 248576 AF XY: 0.00159

Gnomad AFR exome AF: 0.000557

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000510

Gnomad NFE exome AF: 0.00243

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00248 AC: 3629 AN: 1461762 Hom.: 6 Cov.: 34 AF XY: 0.00241 AC XY: 1752 AN XY: 727190

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.00271 AC: 121 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86252

European-Finnish (FIN) AF: 0.000506 AC: 27 AN: 53332

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00298 AC: 3317 AN: 1111982

Other (OTH) AF: 0.00215 AC: 130 AN: 60392

GnomAD4 genome AF: 0.00220 AC: 335 AN: 152308 Hom.: 1 Cov.: 32 AF XY: 0.00207 AC XY: 154 AN XY: 74464

African (AFR) AF: 0.000770 AC: 32 AN: 41570

American (AMR) AF: 0.00510 AC: 78 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00303 AC: 206 AN: 68034

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00234 Hom.: 0

Bravo AF: 0.00235

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00147 AC: 178

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00251

EpiControl AF: 0.00237

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	2	MYH9-related disorder (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 17 (1)
-	-	1	Autosomal dominant nonsyndromic hearing loss 17;C5200934:Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss (1)
-	1	-	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.060
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.67	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.013	D
Sift4G	Benign	0.41	T
Polyphen		0.53	P
Vest4		0.46
MVP		0.86
MPC		1.0
ClinPred		0.018	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.31
Mutation Taster		=91/9	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: rs56200894; hg19: chr22-36745275;