rs33969260

chr17-10393169-G-Achr17-10393169-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002472.3(MYH8):c.5208C>T(p.Asp1736=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,613,884 control chromosomes in the GnomAD database, including 41,996 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2878 hom., cov: 32)
  • Exomes 𝑓: 0.22 (39118 hom.)
• Consequence: MYH8 NM_002472.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0750

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 17-10393169-G-A is Benign according to our data. Variant chr17-10393169-G-A is described in ClinVar as [Benign]. Clinvar id is 129679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10393169-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.075 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH8	NM_002472.3	c.5208C>T	p.Asp1736=	synonymous_variant	36/40	ENST00000403437.2
MYHAS	NR_125367.1	n.76+9962G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH8	ENST00000403437.2	c.5208C>T	p.Asp1736=	synonymous_variant	36/40	5	NM_002472.3	P1
	ENST00000399342.6	n.76+9962G>A		intron_variant, non_coding_transcript_variant		3
	ENST00000581304.1	n.52+9962G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25559 AN: 152002 Hom.: 2879 Cov.: 32

Gnomad AFR AF: 0.0509

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0710

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.197

GnomAD3 exomes AF: 0.175 AC: 43906 AN: 251370 Hom.: 4929 AF XY: 0.178 AC XY: 24154 AN XY: 135886

Gnomad AFR exome AF: 0.0445

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0759

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.251

Gnomad OTH exome AF: 0.217

GnomAD4 exome AF: 0.221 AC: 322319 AN: 1461764 Hom.: 39118 Cov.: 37 AF XY: 0.217 AC XY: 158148 AN XY: 727180

Gnomad4 AFR exome AF: 0.0434

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.262

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.0800

Gnomad4 FIN exome AF: 0.209

Gnomad4 NFE exome AF: 0.249

Gnomad4 OTH exome AF: 0.204

GnomAD4 genome AF: 0.168 AC: 25557 AN: 152120 Hom.: 2878 Cov.: 32 AF XY: 0.164 AC XY: 12158 AN XY: 74360

Gnomad4 AFR AF: 0.0508

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.261

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.0710

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.249

Gnomad4 OTH AF: 0.196

Alfa AF: 0.222 Hom.: 2106

Bravo AF: 0.163

Asia WGS AF: 0.0420 AC: 147 AN: 3478

EpiCase AF: 0.259

EpiControl AF: 0.256

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

Hecht syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	4.7
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs33969260; hg19: chr17-10296486; COSMIC: COSV67960032;