NM_002472.3:c.5074T>C

Variant names:

• chr17-10394341-A-G
• rs8069834
• NM_002472.3:c.5074T>C

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.5074T>C​(p.Trp1692Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 1,613,742 control chromosomes in the GnomAD database, including 263,923 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (27438 hom., cov: 30)
  • Exomes 𝑓: 0.56 (236485 hom.)
• Consequence: MYH8 NM_002472.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.738
• Publications: 28 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=1.2877016E-6).
• BP6: Variant 17-10394341-A-G is Benign according to our data. Variant chr17-10394341-A-G is described in ClinVar as Benign. ClinVar VariationId is 129678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.717 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002472.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH8	NM_002472.3	MANE Select	c.5074T>C	p.Trp1692Arg	missense	Exon 35 of 40	NP_002463.2	P13535
	MYHAS	NR_125367.1		n.76+11134A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH8	ENST00000403437.2	TSL:5 MANE Select	c.5074T>C	p.Trp1692Arg	missense	Exon 35 of 40	ENSP00000384330.2	P13535
	MYHAS	ENST00000399342.6	TSL:3	n.76+11134A>G		intron	N/A
	MYHAS	ENST00000581304.2	TSL:3	n.52+11134A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89225 AN: 151748 Hom.: 27416 Cov.: 30

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.588

Gnomad OTH AF: 0.610

GnomAD2 exomes AF: 0.500 AC: 125849 AN: 251466 AF XY: 0.499

Gnomad AFR exome AF: 0.732

Gnomad AMR exome AF: 0.395

Gnomad ASJ exome AF: 0.542

Gnomad EAS exome AF: 0.113

Gnomad FIN exome AF: 0.523

Gnomad NFE exome AF: 0.591

Gnomad OTH exome AF: 0.543

GnomAD4 exome AF: 0.559 AC: 817696 AN: 1461876 Hom.: 236485 Cov.: 95 AF XY: 0.554 AC XY: 403049 AN XY: 727234

African (AFR) AF: 0.734 AC: 24587 AN: 33480

American (AMR) AF: 0.413 AC: 18488 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 14120 AN: 26136

East Asian (EAS) AF: 0.151 AC: 5979 AN: 39700

South Asian (SAS) AF: 0.359 AC: 30938 AN: 86258

European-Finnish (FIN) AF: 0.534 AC: 28508 AN: 53420

Middle Eastern (MID) AF: 0.566 AC: 3264 AN: 5764

European-Non Finnish (NFE) AF: 0.592 AC: 658726 AN: 1112000

Other (OTH) AF: 0.548 AC: 33086 AN: 60396

GnomAD4 genome AF: 0.588 AC: 89296 AN: 151866 Hom.: 27438 Cov.: 30 AF XY: 0.575 AC XY: 42635 AN XY: 74192

African (AFR) AF: 0.723 AC: 29936 AN: 41382

American (AMR) AF: 0.512 AC: 7809 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 1882 AN: 3468

East Asian (EAS) AF: 0.134 AC: 689 AN: 5156

South Asian (SAS) AF: 0.344 AC: 1655 AN: 4816

European-Finnish (FIN) AF: 0.519 AC: 5461 AN: 10528

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.588 AC: 39942 AN: 67956

Other (OTH) AF: 0.608 AC: 1283 AN: 2110

Alfa AF: 0.590 Hom.: 17474

Bravo AF: 0.597

TwinsUK AF: 0.598 AC: 2219

ALSPAC AF: 0.592 AC: 2282

ESP6500AA AF: 0.721 AC: 3176

ESP6500EA AF: 0.583 AC: 5013

ExAC AF: 0.509 AC: 61857

Asia WGS AF: 0.281 AC: 983 AN: 3478

EpiCase AF: 0.600

EpiControl AF: 0.597

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Hecht syndrome (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.4
DANN	Benign	0.77
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-4.2	N
PhyloP100		0.74
PrimateAI	Benign	0.36	T
PROVEAN	Benign	5.3	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.031
MutPred		0.15		Gain of disorder (P = 0.0122)
MPC		0.35
ClinPred		0.0038	T
GERP RS		1.8
Varity_R		0.052
gMVP		0.33
Mutation Taster		=91/9	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: rs8069834; hg19: chr17-10297658; COSMIC: COSV67960003;