MYH2 p.Phe156Phe

Variant names:

• chr17-10545383-G-A
• rs1555572051
• NM_017534.6:c.468C>T
• MYH2 p.Phe156Phe

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_ModerateBP6_Moderate

The NM_017534.6(MYH2):c.468C>T (p.Phe156Phe) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.13). Variant has been reported in ClinVar as Benign/Likely Benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH2 NM_017534.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 8.13
• Publications: 0 publications found

Genes affected

MYH2 (HGNC:7572): (myosin heavy chain 2) 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 found in a cluster of myosin heavy chain genes on chromosome 17. A mutation in this gene results in inclusion body myopathy-3. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Sep 2009]

MYH2 Gene-Disease associations (from GenCC):

• myopathy, proximal, and ophthalmoplegia

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Illumina
• childhood-onset autosomal recessive myopathy with external ophthalmoplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MYHAS (HGNC:50609): ()

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_017534.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MYH2 NM_017534.6	MANE Select	c.468C>T p.Phe156Phe	synonymous	Exon 5 of 40	Prot: NP_060004.3
	MYH2 NM_001100112.2		c.468C>T p.Phe156Phe	synonymous	Exon 5 of 40	Prot: NP_001093582.1 UniProt:
	MYHAS NR_125367.1		n.168-22154G>A	intron	Intron 2 of 10	Prot:

MYH2 NM_017534.6

MANE Select

HGVSc / HGVSpc.468C>Tp.Phe156Phe

Exon rankExon 5 of 40

synonymous

Prot: NP_060004.3

MYH2 NM_001100112.2

HGVSc / HGVSpc.468C>Tp.Phe156Phe

Exon rankExon 5 of 40

synonymous

Prot: NP_001093582.1UniProt: Q9UKX2-1

MYHAS NR_125367.1

HGVSc / HGVSpn.168-22154G>A

Exon rankIntron 2 of 10

intron

Prot:

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MYH2 ENST00000245503.10	TSL:1MANE Select	c.468C>T p.Phe156Phe	synonymous	Exon 5 of 40	Prot: ENSP00000245503.5 UniProt:
	MYH2 ENST00000532183.6	TSL:1	c.468C>T p.Phe156Phe	synonymous	Exon 4 of 17	Prot: ENSP00000433944.1 UniProt:
	MYH2 ENST00000622564.4	TSL:1	c.468C>T p.Phe156Phe	synonymous	Exon 5 of 18	Prot: ENSP00000482463.1 UniProt:

MYH2 ENST00000245503.10

TSL:1MANE Select

HGVSc / HGVSpc.468C>Tp.Phe156Phe

Exon rankExon 5 of 40

synonymous

Prot: ENSP00000245503.5UniProt: Q9UKX2-1

MYH2 ENST00000532183.6

TSL:1

HGVSc / HGVSpc.468C>Tp.Phe156Phe

Exon rankExon 4 of 17

synonymous

Prot: ENSP00000433944.1UniProt: Q9UKX2-2

MYH2 ENST00000622564.4

TSL:1

HGVSc / HGVSpc.468C>Tp.Phe156Phe

Exon rankExon 5 of 18

synonymous

Prot: ENSP00000482463.1UniProt: Q9UKX2-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Myopathy, proximal, and ophthalmoplegia (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	19
BayesDel_noAF	Benign	-0.33
CADD	Benign	12
DANN	Benign	0.79
GPN-Star LLR	N/A	-2.7
GPN-Star score	N/A	2.7
PhyloP100	Pathogenic	8.1

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1555572051;

hg19: chr17-10448700;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar