rs34953692

Positions:

chr17-10399648-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_002472.3(MYH8):c.3757C>T(p.Arg1253Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,613,962 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 7 hom. )

Consequence

MYH8
NM_002472.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.91

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 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=0.018030345).

BP6

Variant 17-10399648-G-A is Benign according to our data. Variant chr17-10399648-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10399648-G-A is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 679 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH8	NM_002472.3 linkuse as main transcript	c.3757C>T	p.Arg1253Cys	missense_variant	28/40	ENST00000403437.2	NP_002463.2
MYHAS	NR_125367.1 linkuse as main transcript	n.77-6500G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MYH8	ENST00000403437.2 linkuse as main transcript	c.3757C>T	p.Arg1253Cys	missense_variant	28/40	5	NM_002472.3	ENSP00000384330	P1
	ENST00000399342.6 linkuse as main transcript	n.77-6500G>A		intron_variant, non_coding_transcript_variant		3
	ENST00000581304.1 linkuse as main transcript	n.53-6500G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00445

AC:

676

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00100

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.00204

AC:

512

AN:

251494

Hom.:

AF XY:

0.00181

AC XY:

246

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0133

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.00526

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00176

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000905

Gnomad OTH exome

AF:

0.00195

GnomAD4 exome

AF:

0.00114

AC:

1660

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

851

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0140

Gnomad4 AMR exome

AF:

0.00197

Gnomad4 ASJ exome

AF:

0.00471

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00240

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000540

Gnomad4 OTH exome

AF:

0.00217

GnomAD4 genome

AF:

0.00446

AC:

679

AN:

152144

Hom.:

Cov.:

AF XY:

0.00399

AC XY:

297

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0130

Gnomad4 AMR

AF:

0.00275

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00146

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.00101

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00179

Hom.:

Bravo

AF:

0.00482

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0118

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00227

AC:

276

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00202

EpiControl

AF:

0.00124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2019	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 05, 2017

- -

Hecht syndrome

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.63

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.018

MetaSVM

Uncertain

0.070

MutationAssessor

Pathogenic

4.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.3

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.78

MVP

0.88

MPC

0.31

ClinPred

0.051

GERP RS

4.4

Varity_R

0.39

gMVP

0.40

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