chr17-10404366-T-C

Variant names:

• chr17-10404366-T-C
• rs80168976
• NM_002472.3:c.2652A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002472.3(MYH8):​c.2652A>G​(p.Leu884Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,614,042 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (9 hom.)
• Consequence: MYH8 NM_002472.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.39
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 17-10404366-T-C is Benign according to our data. Variant chr17-10404366-T-C is described in ClinVar as Benign. ClinVar VariationId is 258718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.39 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00561 (854/152270) while in subpopulation AFR AF = 0.0197 (819/41558). AF 95% confidence interval is 0.0186. There are 8 homozygotes in GnomAd4. There are 390 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 854 AD gene.

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.2652A>G	p.Leu884Leu	synonymous	Exon 22 of 40	NP_002463.2
	MYHAS	NR_125367.1		n.77-1782T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH8	ENST00000403437.2	TSL:5 MANE Select	c.2652A>G	p.Leu884Leu	synonymous	Exon 22 of 40	ENSP00000384330.2
	MYHAS	ENST00000399342.6	TSL:3	n.77-1782T>C		intron	N/A
	MYHAS	ENST00000581304.2	TSL:3	n.53-1782T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00555 AC: 845 AN: 152152 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00150 AC: 376 AN: 251424 AF XY: 0.00108

Gnomad AFR exome AF: 0.0212

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000548 AC: 801 AN: 1461772 Hom.: 9 Cov.: 31 AF XY: 0.000496 AC XY: 361 AN XY: 727182

African (AFR) AF: 0.0197 AC: 661 AN: 33478

American (AMR) AF: 0.000917 AC: 41 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111906

Other (OTH) AF: 0.00136 AC: 82 AN: 60390

GnomAD4 genome AF: 0.00561 AC: 854 AN: 152270 Hom.: 8 Cov.: 32 AF XY: 0.00524 AC XY: 390 AN XY: 74454

African (AFR) AF: 0.0197 AC: 819 AN: 41558

American (AMR) AF: 0.00144 AC: 22 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00267 Hom.: 4

Bravo AF: 0.00664

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.9
DANN	Benign	0.65
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism

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: rs80168976; hg19: chr17-10307683;