chr17-10409155-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002472.3(MYH8):​c.1907C>G​(p.Ala636Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A636V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH8 NM_002472.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.49
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044632047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH8	NM_002472.3	c.1907C>G	p.Ala636Gly	missense_variant	Exon 17 of 40	ENST00000403437.2	NP_002463.2
MYHAS	NR_125367.1	n.167+2917G>C		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH8	ENST00000403437.2	c.1907C>G	p.Ala636Gly	missense_variant	Exon 17 of 40	5	NM_002472.3	ENSP00000384330.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.37
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.0	N
PhyloP100		1.5
PrimateAI	Benign	0.41	T
PROVEAN	Benign	2.7	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	0.92	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.29		Loss of stability (P = 0.0215);
MVP		0.48
MPC		0.20
ClinPred		0.075	T
GERP RS		5.2
Varity_R		0.060
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;