rs2157257

Variant names:

• chr22-36312293-A-G
• rs2157257
• NM_002473.6:c.1555-71T>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.1555-71T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.62 in 1,537,632 control chromosomes in the GnomAD database, including 309,404 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (23360 hom., cov: 31)
  • Exomes 𝑓: 0.63 (286044 hom.)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.344
• Publications: 12 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=-0.83).
• BP6: Variant 22-36312293-A-G is Benign according to our data. Variant chr22-36312293-A-G is described in ClinVar as Benign. ClinVar VariationId is 1243503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.1555-71T>C		intron_variant	Intron 13 of 40	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.1555-71T>C		intron_variant	Intron 13 of 40	1	NM_002473.6	ENSP00000216181.6

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78682 AN: 151896 Hom.: 23364 Cov.: 31

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.608

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.541

GnomAD4 exome AF: 0.631 AC: 874468 AN: 1385618 Hom.: 286044 AF XY: 0.626 AC XY: 432093 AN XY: 690724

African (AFR) AF: 0.224 AC: 7077 AN: 31620

American (AMR) AF: 0.630 AC: 26812 AN: 42552

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 13088 AN: 25178

East Asian (EAS) AF: 0.219 AC: 8514 AN: 38792

South Asian (SAS) AF: 0.415 AC: 34654 AN: 83592

European-Finnish (FIN) AF: 0.660 AC: 30792 AN: 46660

Middle Eastern (MID) AF: 0.508 AC: 2836 AN: 5586

European-Non Finnish (NFE) AF: 0.680 AC: 717056 AN: 1053980

Other (OTH) AF: 0.583 AC: 33639 AN: 57658

GnomAD4 genome AF: 0.518 AC: 78685 AN: 152014 Hom.: 23360 Cov.: 31 AF XY: 0.514 AC XY: 38164 AN XY: 74292

African (AFR) AF: 0.238 AC: 9870 AN: 41468

American (AMR) AF: 0.608 AC: 9289 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 1800 AN: 3472

East Asian (EAS) AF: 0.221 AC: 1137 AN: 5152

South Asian (SAS) AF: 0.385 AC: 1854 AN: 4810

European-Finnish (FIN) AF: 0.652 AC: 6887 AN: 10566

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.675 AC: 45874 AN: 67952

Other (OTH) AF: 0.536 AC: 1127 AN: 2104

Alfa AF: 0.599 Hom.: 4638

Bravo AF: 0.504

Asia WGS AF: 0.253 AC: 881 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 89% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 83. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.8
DANN	Benign	0.73
PhyloP100		0.34
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: rs2157257; hg19: chr22-36708338; COSMIC: COSV53395916; COSMIC: COSV53395916;