22-36316765-C-G

Variant names:

• chr22-36316765-C-G
• rs1557536
• NM_002473.6:c.1228-96G>C

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.1228-96G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 1,443,892 control chromosomes in the GnomAD database, including 311,988 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (26094 hom., cov: 30)
  • Exomes 𝑓: 0.65 (285894 hom.)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.10
• Publications: 7 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 (BayesDel_noAF=-0.86).
• BP6: Variant 22-36316765-C-G is Benign according to our data. Variant chr22-36316765-C-G is described in ClinVar as Benign. ClinVar VariationId is 1247060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.693 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	NM_002473.6	MANE Select	c.1228-96G>C		intron	N/A	NP_002464.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	ENST00000216181.11	TSL:1 MANE Select	c.1228-96G>C		intron	N/A	ENSP00000216181.6
	MYH9	ENST00000685801.1		c.1228-96G>C		intron	N/A	ENSP00000510688.1
	MYH9	ENST00000955568.1		c.1228-96G>C		intron	N/A	ENSP00000625627.1

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85082 AN: 151766 Hom.: 26093 Cov.: 30

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.580

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.698

Gnomad OTH AF: 0.585

GnomAD4 exome AF: 0.654 AC: 844984 AN: 1292008 Hom.: 285894 AF XY: 0.648 AC XY: 416898 AN XY: 643718

African (AFR) AF: 0.325 AC: 9659 AN: 29700

American (AMR) AF: 0.653 AC: 24743 AN: 37890

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 14282 AN: 24540

East Asian (EAS) AF: 0.214 AC: 7866 AN: 36810

South Asian (SAS) AF: 0.427 AC: 34259 AN: 80188

European-Finnish (FIN) AF: 0.666 AC: 31575 AN: 47428

Middle Eastern (MID) AF: 0.571 AC: 2216 AN: 3878

European-Non Finnish (NFE) AF: 0.703 AC: 687249 AN: 977322

Other (OTH) AF: 0.611 AC: 33135 AN: 54252

GnomAD4 genome AF: 0.560 AC: 85104 AN: 151884 Hom.: 26094 Cov.: 30 AF XY: 0.555 AC XY: 41178 AN XY: 74246

African (AFR) AF: 0.337 AC: 13932 AN: 41380

American (AMR) AF: 0.632 AC: 9639 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 2013 AN: 3470

East Asian (EAS) AF: 0.215 AC: 1111 AN: 5178

South Asian (SAS) AF: 0.397 AC: 1912 AN: 4818

European-Finnish (FIN) AF: 0.661 AC: 6965 AN: 10540

Middle Eastern (MID) AF: 0.545 AC: 159 AN: 292

European-Non Finnish (NFE) AF: 0.698 AC: 47423 AN: 67930

Other (OTH) AF: 0.579 AC: 1218 AN: 2104

Alfa AF: 0.523 Hom.: 1681

Bravo AF: 0.550

Asia WGS AF: 0.271 AC: 942 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.4
DANN	Benign	0.44
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1557536; hg19: chr22-36712810;