12-80707902-T-G

Variant names:

• chr12-80707902-T-G
• rs776368255
• NM_002469.3:c.183T>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002469.3(MYF6):​c.183T>G​(p.His61Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: MYF6 NM_002469.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.93

Genes affected

MYF6 (HGNC:7566): (myogenic factor 6) The protein encoded by this gene is a probable basic helix-loop-helix (bHLH) DNA binding protein involved in muscle differentiation. The encoded protein likely acts as a heterodimer with another bHLH protein. Defects in this gene are a cause of autosomal dominant centronuclear myopathy (ADCNM). [provided by RefSeq, May 2010]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYF6	NM_002469.3	c.183T>G	p.His61Gln	missense_variant	Exon 1 of 3	ENST00000228641.4	NP_002460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYF6	ENST00000228641.4	c.183T>G	p.His61Gln	missense_variant	Exon 1 of 3	1	NM_002469.3	ENSP00000228641.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251346 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant centronuclear myopathy Uncertain:1

Feb 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 940107). This variant has not been reported in the literature in individuals affected with MYF6-related conditions. This variant is present in population databases (rs776368255, gnomAD 0.0009%). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 61 of the MYF6 protein (p.His61Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.90	D
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.53
Sift	Benign	0.038	D
Sift4G	Benign	0.099	T
Polyphen		1.0	D
Vest4		0.57
MutPred		0.53		Gain of catalytic residue at P65 (P = 0.0016);
MVP		0.85
MPC		1.1
ClinPred		0.91	D
GERP RS		-9.0
Varity_R		0.61
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs776368255; hg19: chr12-81101681;