17-10392944-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_002472.3(MYH8):c.5350C>G(p.Arg1784Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00729 in 1,614,100 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1784W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0047 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (59 hom.)
• Consequence: MYH8 NM_002472.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.467

Genes affected

MYH8 (HGNC:7578): (myosin heavy chain 8) Myosins are actin-based motor proteins that function in the generation of mechanical force in eukaryotic cells. Muscle myosins are heterohexamers composed of 2 myosin heavy chains and 2 pairs of nonidentical myosin light chains. This gene encodes a member of the class II or conventional myosin heavy chains, and functions in skeletal muscle contraction. This gene is predominantly expressed in fetal skeletal muscle. This gene is found in a cluster of myosin heavy chain genes on chromosome 17. A mutation in this gene results in trismus-pseudocamptodactyly syndrome. [provided by RefSeq, Sep 2009]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH8
• BP4: Computational evidence support a benign effect (MetaRNN=0.03230071).
• BP6: Variant 17-10392944-G-C is Benign according to our data. Variant chr17-10392944-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211567.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=3}. Variant chr17-10392944-G-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 711 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH8	NM_002472.3	c.5350C>G	p.Arg1784Gly	missense_variant	37/40	ENST00000403437.2
MYHAS	NR_125367.1	n.76+9737G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH8	ENST00000403437.2	c.5350C>G	p.Arg1784Gly	missense_variant	37/40	5	NM_002472.3	P1
	ENST00000399342.6	n.76+9737G>C		intron_variant, non_coding_transcript_variant		3
	ENST00000581304.1	n.52+9737G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 711 AN: 152090 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00726

Gnomad FIN AF: 0.00481

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00750

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00530 AC: 1334 AN: 251490 Hom.: 9 AF XY: 0.00547 AC XY: 743 AN XY: 135920

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00588

Gnomad FIN exome AF: 0.00513

Gnomad NFE exome AF: 0.00764

Gnomad OTH exome AF: 0.00717

GnomAD4 exome AF: 0.00756 AC: 11058 AN: 1461892 Hom.: 59 Cov.: 33 AF XY: 0.00740 AC XY: 5384 AN XY: 727246

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.00386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00596

Gnomad4 FIN exome AF: 0.00569

Gnomad4 NFE exome AF: 0.00860

Gnomad4 OTH exome AF: 0.00732

GnomAD4 genome AF: 0.00466 AC: 709 AN: 152208 Hom.: 3 Cov.: 32 AF XY: 0.00462 AC XY: 344 AN XY: 74418

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00686

Gnomad4 FIN AF: 0.00481

Gnomad4 NFE AF: 0.00750

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00281 Hom.: 0

Bravo AF: 0.00412

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00570 AC: 49

ExAC AF: 0.00604 AC: 733

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00703

EpiControl AF: 0.00616

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2020	This variant is associated with the following publications: (PMID: 29565416) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	MYH8: PP3, BS2 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hecht syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2014

Based on data from the NHLBI Exome Sequencing Project (ESP), the G-allele has an overall frequency of approximately 0.42% (45/10754) total alleles studied. The G-allele was observed in 0.58% (41/7016) European American alleles and in 0.11% (4/3738) African American alleles studied and was not observed in the homozygous state out of 5377 individuals studied. Based on data from the 1000 Genomes Project, the G-allele has an overall frequency of approximately 0.32% (7/2188) and the highest frequency was in 1.82% (2/110) 1.82% Puerto Rican chromosomes studied.The R1784 amino acid is highly conserved among available vertebrate species.This alteration is predicted to be probably damaging with a score of 0.961 (sensitivity: 0.62; specificity: 0.92)This alteration is predicted to be deleterious with a score of 0.000 (conservation: 3.05) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	0.0054	T
BayesDel_noAF	Pathogenic	0.24
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.032	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.027	D
Polyphen		0.99	D
Vest4		0.86
MVP		0.82
MPC		0.82
ClinPred		0.032	T
GERP RS		3.0
Varity_R		0.66
gMVP		0.85

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: rs141215006; hg19: chr17-10296261; COSMIC: COSV67965264;