rs34693726

Variant names:

• chr17-10409155-G-A
• rs34693726
• NM_002472.3:c.1907C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-10409155-G-A
• chr17-10409155-G-C
• chr17-10409155-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002472.3(MYH8):​c.1907C>T​(p.Ala636Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0576 in 1,613,654 control chromosomes in the GnomAD database, including 3,088 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A636S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.054 (248 hom., cov: 33)
  • Exomes 𝑓: 0.058 (2840 hom.)
• Consequence: MYH8 NM_002472.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.49
• Publications: 14 publications found

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]

MYHAS (HGNC:50609): (myosin heavy chain gene cluster antisense RNA) Predicted to enable primary miRNA binding activity. Predicted to be involved in response to muscle activity and skeletal muscle fiber development. Predicted to act upstream of or within with a positive effect on gene expression. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019810796).
• BP6: Variant 17-10409155-G-A is Benign according to our data. Variant chr17-10409155-G-A is described in ClinVar as Benign. ClinVar VariationId is 129671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH8	NM_002472.3	c.1907C>T	p.Ala636Val	missense_variant	Exon 17 of 40	ENST00000403437.2	NP_002463.2
MYHAS	NR_125367.1	n.167+2917G>A		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH8	ENST00000403437.2	c.1907C>T	p.Ala636Val	missense_variant	Exon 17 of 40	5	NM_002472.3	ENSP00000384330.2

Frequencies

GnomAD3 genomes AF: 0.0535 AC: 8130 AN: 152048 Hom.: 245 Cov.: 33

Gnomad AFR AF: 0.0418

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0475

Gnomad ASJ AF: 0.0792

Gnomad EAS AF: 0.0410

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0529

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.0564

Gnomad OTH AF: 0.0679

GnomAD2 exomes AF: 0.0589 AC: 14805 AN: 251236 AF XY: 0.0624

Gnomad AFR exome AF: 0.0403

Gnomad AMR exome AF: 0.0439

Gnomad ASJ exome AF: 0.0800

Gnomad EAS exome AF: 0.0357

Gnomad FIN exome AF: 0.0546

Gnomad NFE exome AF: 0.0549

Gnomad OTH exome AF: 0.0588

GnomAD4 exome AF: 0.0581 AC: 84872 AN: 1461488 Hom.: 2840 Cov.: 32 AF XY: 0.0596 AC XY: 43357 AN XY: 727098

African (AFR) AF: 0.0432 AC: 1446 AN: 33472

American (AMR) AF: 0.0443 AC: 1981 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0811 AC: 2118 AN: 26130

East Asian (EAS) AF: 0.0356 AC: 1415 AN: 39694

South Asian (SAS) AF: 0.109 AC: 9438 AN: 86242

European-Finnish (FIN) AF: 0.0538 AC: 2872 AN: 53416

Middle Eastern (MID) AF: 0.0560 AC: 323 AN: 5768

European-Non Finnish (NFE) AF: 0.0554 AC: 61598 AN: 1111662

Other (OTH) AF: 0.0610 AC: 3681 AN: 60380

GnomAD4 genome AF: 0.0536 AC: 8152 AN: 152166 Hom.: 248 Cov.: 33 AF XY: 0.0549 AC XY: 4082 AN XY: 74370

African (AFR) AF: 0.0421 AC: 1748 AN: 41508

American (AMR) AF: 0.0475 AC: 726 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0792 AC: 275 AN: 3472

East Asian (EAS) AF: 0.0407 AC: 211 AN: 5184

South Asian (SAS) AF: 0.121 AC: 583 AN: 4826

European-Finnish (FIN) AF: 0.0529 AC: 559 AN: 10558

Middle Eastern (MID) AF: 0.0685 AC: 20 AN: 292

European-Non Finnish (NFE) AF: 0.0564 AC: 3833 AN: 68010

Other (OTH) AF: 0.0682 AC: 144 AN: 2112

Alfa AF: 0.0541 Hom.: 804

Bravo AF: 0.0508

TwinsUK AF: 0.0520 AC: 193

ALSPAC AF: 0.0522 AC: 201

ESP6500AA AF: 0.0452 AC: 199

ESP6500EA AF: 0.0610 AC: 525

ExAC AF: 0.0591 AC: 7178

Asia WGS AF: 0.0900 AC: 313 AN: 3478

EpiCase AF: 0.0575

EpiControl AF: 0.0577

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 28, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hecht syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.96	L
PhyloP100		1.5
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.17
Sift	Benign	0.048	D
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.097
MPC		0.20
ClinPred		0.029	T
GERP RS		5.2
Varity_R		0.088
gMVP		0.15
Mutation Taster		=93/7	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: rs34693726; hg19: chr17-10312472; COSMIC: COSV67966006;