NM_005592.4:c.46G>C

Variant names:

• chr9-110668950-G-C
• rs765521756
• NM_005592.4:c.46G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005592.4(MUSK):​c.46G>C​(p.Val16Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.42
• Publications: 2 publications found

Genes affected

MUSK (HGNC:7525): (muscle associated receptor tyrosine kinase) This gene encodes a muscle-specific tyrosine kinase receptor. The encoded protein may play a role in clustering of the acetylcholine receptor in the postsynaptic neuromuscular junction. Mutations in this gene have been associated with congenital myasthenic syndrome. Alternatively spliced transcript variants have been described.[provided by RefSeq, Oct 2009]

MUSK Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 9

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17673412).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4	c.46G>C	p.Val16Leu	missense_variant	Exon 1 of 15	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.46G>C	p.Val16Leu	missense_variant	Exon 1 of 15	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7	c.46G>C	p.Val16Leu	missense_variant	Exon 1 of 14	5		ENSP00000393608.3
MUSK	ENST00000189978.10	c.46G>C	p.Val16Leu	missense_variant	Exon 1 of 14	5		ENSP00000189978.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249192 AF XY: 0.00000740

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461510 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727042

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111714

Other (OTH) AF: 0.00 AC: 0 AN: 60372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.46G>C (p.V16L) alteration is located in exon 1 (coding exon 1) of the MUSK gene. This alteration results from a G to C substitution at nucleotide position 46, causing the valine (V) at amino acid position 16 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;.;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T;T;T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-0.81	N;.;N;.
PhyloP100		4.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.63	N;N;N;.
REVEL	Benign	0.093
Sift	Uncertain	0.024	D;D;D;.
Sift4G	Benign	0.20	T;T;T;T
Polyphen		0.0040	B;.;.;.
Vest4		0.17
MutPred		0.40		Loss of catalytic residue at V16 (P = 0.1733);Loss of catalytic residue at V16 (P = 0.1733);Loss of catalytic residue at V16 (P = 0.1733);Loss of catalytic residue at V16 (P = 0.1733);
MVP		0.57
MPC		0.16
ClinPred		0.47	T
GERP RS		5.2
PromoterAI		0.085	Neutral
Varity_R		0.17
gMVP		0.36
Mutation Taster		=263/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs765521756; hg19: chr9-113431230; COSMIC: COSV51894225;