rs138992963

Variant names:

• chr17-10396932-G-A
• rs138992963
• NM_002472.3:c.4233C>T

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.4233C>T​(p.Asn1411Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,614,160 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (27 hom.)
• Consequence: MYH8 NM_002472.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.47
• 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=-0.55).
• BP6: Variant 17-10396932-G-A is Benign according to our data. Variant chr17-10396932-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0114 (1740/152268) while in subpopulation AFR AF = 0.0398 (1653/41524). AF 95% confidence interval is 0.0382. There are 38 homozygotes in GnomAd4. There are 786 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1740 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.4233C>T	p.Asn1411Asn	synonymous	Exon 31 of 40	NP_002463.2	P13535
	MYHAS	NR_125367.1		n.77-9216G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH8	ENST00000403437.2	TSL:5 MANE Select	c.4233C>T	p.Asn1411Asn	synonymous	Exon 31 of 40	ENSP00000384330.2	P13535
	MYHAS	ENST00000399342.6	TSL:3	n.77-9216G>A		intron	N/A
	MYHAS	ENST00000581304.2	TSL:3	n.53-9216G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1737 AN: 152150 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.0399

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00315 AC: 792 AN: 251484 AF XY: 0.00238

Gnomad AFR exome AF: 0.0425

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00116 AC: 1691 AN: 1461892 Hom.: 27 Cov.: 33 AF XY: 0.00102 AC XY: 739 AN XY: 727248

African (AFR) AF: 0.0391 AC: 1309 AN: 33480

American (AMR) AF: 0.00226 AC: 101 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53418

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.0000926 AC: 103 AN: 1112012

Other (OTH) AF: 0.00258 AC: 156 AN: 60396

GnomAD4 genome AF: 0.0114 AC: 1740 AN: 152268 Hom.: 38 Cov.: 32 AF XY: 0.0106 AC XY: 786 AN XY: 74454

African (AFR) AF: 0.0398 AC: 1653 AN: 41524

American (AMR) AF: 0.00340 AC: 52 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68016

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.00540 Hom.: 5

Bravo AF: 0.0129

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Hecht syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.11
DANN	Benign	0.81
PhyloP100		-1.5
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: rs138992963; hg19: chr17-10300249; COSMIC: COSV67973122;