NM_002473.6:c.2977-35C>G

Variant names:

• chr22-36299077-G-C
• rs16996650
• NM_002473.6:c.2977-35C>G

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.2977-35C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0323 in 1,613,042 control chromosomes in the GnomAD database, including 1,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (117 hom., cov: 32)
  • Exomes 𝑓: 0.032 (1058 hom.)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.622
• Publications: 3 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 22-36299077-G-C is Benign according to our data. Variant chr22-36299077-G-C is described in ClinVar as Benign. ClinVar VariationId is 258738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.091 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.2977-35C>G		intron_variant	Intron 23 of 40	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.2977-35C>G		intron_variant	Intron 23 of 40	1	NM_002473.6	ENSP00000216181.6
MYH9	ENST00000685801.1	c.3040-35C>G		intron_variant	Intron 24 of 41			ENSP00000510688.1
MYH9	ENST00000691109.1	n.3272-35C>G		intron_variant	Intron 17 of 34

Frequencies

GnomAD3 genomes AF: 0.0309 AC: 4697 AN: 152044 Hom.: 116 Cov.: 32

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0220

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.0988

Gnomad SAS AF: 0.0740

Gnomad FIN AF: 0.0574

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0316

GnomAD2 exomes AF: 0.0381 AC: 9559 AN: 251214 AF XY: 0.0400

Gnomad AFR exome AF: 0.0206

Gnomad AMR exome AF: 0.0158

Gnomad ASJ exome AF: 0.0178

Gnomad EAS exome AF: 0.0919

Gnomad FIN exome AF: 0.0492

Gnomad NFE exome AF: 0.0285

Gnomad OTH exome AF: 0.0323

GnomAD4 exome AF: 0.0324 AC: 47350 AN: 1460880 Hom.: 1058 Cov.: 32 AF XY: 0.0335 AC XY: 24315 AN XY: 726820

African (AFR) AF: 0.0211 AC: 705 AN: 33422

American (AMR) AF: 0.0158 AC: 708 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0163 AC: 426 AN: 26124

East Asian (EAS) AF: 0.105 AC: 4176 AN: 39676

South Asian (SAS) AF: 0.0700 AC: 6029 AN: 86190

European-Finnish (FIN) AF: 0.0504 AC: 2669 AN: 53008

Middle Eastern (MID) AF: 0.0235 AC: 135 AN: 5756

European-Non Finnish (NFE) AF: 0.0274 AC: 30456 AN: 1111650

Other (OTH) AF: 0.0339 AC: 2046 AN: 60356

GnomAD4 genome AF: 0.0309 AC: 4705 AN: 152162 Hom.: 117 Cov.: 32 AF XY: 0.0324 AC XY: 2413 AN XY: 74394

African (AFR) AF: 0.0224 AC: 930 AN: 41460

American (AMR) AF: 0.0222 AC: 339 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3472

East Asian (EAS) AF: 0.0981 AC: 508 AN: 5180

South Asian (SAS) AF: 0.0747 AC: 360 AN: 4820

European-Finnish (FIN) AF: 0.0574 AC: 608 AN: 10588

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0270 AC: 1838 AN: 68022

Other (OTH) AF: 0.0308 AC: 65 AN: 2110

Alfa AF: 0.0159 Hom.: 9

Bravo AF: 0.0280

Asia WGS AF: 0.0850 AC: 296 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 29, 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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.044
DANN	Benign	0.36
PhyloP100		-0.62
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: rs16996650; hg19: chr22-36695123; COSMIC: COSV53386647; COSMIC: COSV53386647;