17-10392944-G-C

Position:

chr17-10392944-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

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).

Frequency

Genomes: 𝑓 0.0047 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0076 ( 59 hom. )

Consequence

MYH8
NM_002472.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.467

Variant links:

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]

MYH8 links:

ENSG00000272736 (HGNC:):

ENSG00000272736 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH8. . Gene score misZ 0.34953 (greater than the threshold 3.09). Trascript score misZ 3.2125 (greater than threshold 3.09). GenCC has associacion of gene with trismus-pseudocamptodactyly syndrome, Carney complex - trismus - pseudocamptodactyly syndrome.

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 GnomAd4 at 709 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH8	NM_002472.3 linkuse as main transcript	c.5350C>G	p.Arg1784Gly	missense_variant	37/40	ENST00000403437.2	NP_002463.2	P13535
MYHAS	NR_125367.1 linkuse as main transcript	n.76+9737G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYH8	ENST00000403437.2 linkuse as main transcript	c.5350C>G	p.Arg1784Gly	missense_variant	37/40	5	NM_002472.3	ENSP00000384330.2	P13535
ENSG00000272736	ENST00000399342.6 linkuse as main transcript	n.76+9737G>C		intron_variant		3
ENSG00000272736	ENST00000581304.1 linkuse as main transcript	n.52+9737G>C		intron_variant		3
MYHAS	ENST00000587182.2 linkuse as main transcript	n.64+9737G>C		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00467

AC:

711

AN:

152090

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00547

AC XY:

743

AN XY:

135920

show subpopulations

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.:

Cov.:

AF XY:

0.00740

AC XY:

5384

AN XY:

727246

show subpopulations

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.:

Cov.:

AF XY:

0.00462

AC XY:

344

AN XY:

74418

show subpopulations

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.:

Bravo

AF:

0.00412

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00570

AC:

ExAC

AF:

0.00604

AC:

733

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00703

EpiControl

AF:

0.00616

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

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	Labcorp Genetics (formerly Invitae), Labcorp	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	Mendelics	May 28, 2019	- -
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. -

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

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.032

MetaSVM

Uncertain

0.38

MutationAssessor

Pathogenic

3.1

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.027

Polyphen

0.99

Vest4

0.86

MVP

0.82

MPC

0.82

ClinPred

0.032

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over