17-10392606-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP6 BS2

The NM_002472.3(MYH8):c.5504G>A(p.Arg1835His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,614,148 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: MYH8 NM_002472.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.64

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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH8
• BP6: Variant 17-10392606-C-T is Benign according to our data. Variant chr17-10392606-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 722469.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH8	NM_002472.3	c.5504G>A	p.Arg1835His	missense_variant	38/40	ENST00000403437.2
MYHAS	NR_125367.1	n.76+9399C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH8	ENST00000403437.2	c.5504G>A	p.Arg1835His	missense_variant	38/40	5	NM_002472.3	P1
	ENST00000399342.6	n.76+9399C>T		intron_variant, non_coding_transcript_variant		3
	ENST00000581304.1	n.52+9399C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000915 AC: 23 AN: 251482 Hom.: 0 AF XY: 0.000132 AC XY: 18 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000554 AC: 81 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.0000701 AC XY: 51 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000730

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74454

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The c.5504G>A (p.R1835H) alteration is located in exon 38 (coding exon 36) of the MYH8 gene. This alteration results from a G to A substitution at nucleotide position 5504, causing the arginine (R) at amino acid position 1835 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	0.10
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.43
Sift	Benign	0.033	D
Sift4G	Uncertain	0.047	D
Polyphen		0.068	B
Vest4		0.65
MutPred		0.69		Loss of MoRF binding (P = 0.03);
MVP		0.79
MPC		0.26
ClinPred		0.36	T
GERP RS		4.1
Varity_R		0.19
gMVP		0.28

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

Other links and lift over

dbSNP: rs777055080; hg19: chr17-10295923; COSMIC: COSV67959512;