22-36301679-T-C

Variant names:

• chr22-36301679-T-C
• rs199505086
• NM_002473.6:c.2500-14A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002473.6(MYH9):​c.2500-14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000446 in 1,612,298 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (2 hom.)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.44

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 22-36301679-T-C is Benign according to our data. Variant chr22-36301679-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 164451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000335 (51/152136) while in subpopulation SAS AF= 0.000829 (4/4826). AF 95% confidence interval is 0.000283. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.2500-14A>G		intron_variant	Intron 20 of 40	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.2500-14A>G		intron_variant	Intron 20 of 40	1	NM_002473.6	ENSP00000216181.6
MYH9	ENST00000685801.1	c.2563-14A>G		intron_variant	Intron 21 of 41			ENSP00000510688.1
MYH9	ENST00000495928.1	n.36A>G		non_coding_transcript_exon_variant	Exon 1 of 2	2
MYH9	ENST00000691109.1	n.2795-14A>G		intron_variant	Intron 14 of 34

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152136 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000836 AC: 208 AN: 248742 Hom.: 0 AF XY: 0.000971 AC XY: 131 AN XY: 134882

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00909

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000399

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000457 AC: 668 AN: 1460162 Hom.: 2 Cov.: 32 AF XY: 0.000556 AC XY: 404 AN XY: 726456

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00869

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00154

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.000209

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152136 Hom.: 0 Cov.: 33 AF XY: 0.000484 AC XY: 36 AN XY: 74322

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.000577

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00141 Hom.: 0

Bravo AF: 0.000389

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Nov 12, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.2500-14A>G variant in intron 20 of MYH9: This variant is not expected to have clinical significance because it does not affect the conserved positions of the 3' splice site and computational tools do not suggest an impact to splicing. In addition, it has also been identified in 0.12% (20/16438) of South Asian chromos omes and in 0.1% (54/65316) of European chromosomes by the Exome Aggregation Con sortium (ExAC, http://exac.broadinstitute.org;dbSNP rs199505086). -

Autosomal dominant nonsyndromic hearing loss 17 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Autosomal dominant nonsyndromic hearing loss 17;C5200934:Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Benign:1

Oct 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MYH9-related disorder Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.026
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs199505086; hg19: chr22-36697725;