rs2277648

Variant names:

• chr17-10421663-C-T
• rs2277648
• NM_002472.3:c.-31G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-10421663-C-T
• chr17-10421663-C-A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_002472.3(MYH8):​c.-31G>A variant causes a splice region change. The variant allele was found at a frequency of 0.322 in 152,014 control chromosomes in the GnomAD database, including 9,051 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9051 hom., cov: 32)
  • Exomes 𝑓: 0.33 (0 hom.)
• Consequence: MYH8 NM_002472.3 splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.49
• Publications: 11 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 17-10421663-C-T is Benign according to our data. Variant chr17-10421663-C-T is described in ClinVar as Benign. ClinVar VariationId is 321659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.805 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.-31G>A		splice_region	Exon 2 of 40	NP_002463.2	P13535
	MYH8	NM_002472.3	MANE Select	c.-31G>A		5_prime_UTR	Exon 2 of 40	NP_002463.2	P13535
	MYHAS	NR_125367.1		n.167+15425C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH8	ENST00000403437.2	TSL:5 MANE Select	c.-31G>A		splice_region	Exon 2 of 40	ENSP00000384330.2	P13535
	MYH8	ENST00000403437.2	TSL:5 MANE Select	c.-31G>A		5_prime_UTR	Exon 2 of 40	ENSP00000384330.2	P13535
	MYHAS	ENST00000399342.6	TSL:3	n.206+15386C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48935 AN: 151890 Hom.: 9052 Cov.: 32

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.826

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.299

GnomAD4 exome AF: 0.333 AC: 2 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.333 AC XY: 2 AN XY: 6

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.333 AC: 2 AN: 6

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.322 AC: 48959 AN: 152008 Hom.: 9051 Cov.: 32 AF XY: 0.335 AC XY: 24880 AN XY: 74310

African (AFR) AF: 0.222 AC: 9225 AN: 41476

American (AMR) AF: 0.413 AC: 6304 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1093 AN: 3468

East Asian (EAS) AF: 0.826 AC: 4277 AN: 5180

South Asian (SAS) AF: 0.492 AC: 2375 AN: 4824

European-Finnish (FIN) AF: 0.383 AC: 4038 AN: 10534

Middle Eastern (MID) AF: 0.336 AC: 98 AN: 292

European-Non Finnish (NFE) AF: 0.303 AC: 20595 AN: 67952

Other (OTH) AF: 0.300 AC: 634 AN: 2112

Alfa AF: 0.321 Hom.: 28241

Bravo AF: 0.319

Asia WGS AF: 0.611 AC: 2119 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	0.98
PhyloP100		5.5
PromoterAI		-0.044	Neutral
Mutation Taster		=293/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.10		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: rs2277648; hg19: chr17-10324980;