rs112910113

chr17-10396702-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002472.3(MYH8):c.4379A>G(p.Lys1460Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00106 in 1,614,190 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (10 hom.)
• Consequence: MYH8 NM_002472.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.13

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH8
• BP4: Computational evidence support a benign effect (MetaRNN=0.0069132745).
• BP6: Variant 17-10396702-T-C is Benign according to our data. Variant chr17-10396702-T-C is described in ClinVar as [Benign]. Clinvar id is 258720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0057 (868/152304) while in subpopulation AFR AF= 0.02 (832/41554). AF 95% confidence interval is 0.0189. There are 7 homozygotes in gnomad4. There are 395 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 859 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH8	NM_002472.3	c.4379A>G	p.Lys1460Arg	missense_variant	32/40	ENST00000403437.2
MYHAS	NR_125367.1	n.77-9446T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH8	ENST00000403437.2	c.4379A>G	p.Lys1460Arg	missense_variant	32/40	5	NM_002472.3	P1
	ENST00000399342.6	n.77-9446T>C		intron_variant, non_coding_transcript_variant		3
	ENST00000581304.1	n.53-9446T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00564 AC: 859 AN: 152186 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00154 AC: 386 AN: 251442 Hom.: 4 AF XY: 0.00112 AC XY: 152 AN XY: 135888

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000575 AC: 840 AN: 1461886 Hom.: 10 Cov.: 33 AF XY: 0.000516 AC XY: 375 AN XY: 727246

Gnomad4 AFR exome AF: 0.0207

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00570 AC: 868 AN: 152304 Hom.: 7 Cov.: 32 AF XY: 0.00530 AC XY: 395 AN XY: 74470

Gnomad4 AFR AF: 0.0200

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.000968 Hom.: 4

Bravo AF: 0.00688

ESP6500AA AF: 0.0232 AC: 102

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00199 AC: 242

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.67	D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.27
Sift	Benign	0.14	T
Sift4G	Benign	0.20	T
Polyphen		0.020	B
Vest4		0.061
MVP		0.65
MPC		0.20
ClinPred		0.018	T
GERP RS		1.4
Varity_R		0.052
gMVP		0.21

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: rs112910113; hg19: chr17-10300019;