rs71501643

Variant names:

• chr9-110687097-T-C
• rs71501643
• NM_005592.4:c.207-20T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005592.4(MUSK):​c.207-20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0552 in 1,601,560 control chromosomes in the GnomAD database, including 2,628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (217 hom., cov: 31)
  • Exomes 𝑓: 0.056 (2411 hom.)
• Consequence: MUSK NM_005592.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.404
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-110687097-T-C is Benign according to our data. Variant chr9-110687097-T-C is described in ClinVar as Benign. ClinVar VariationId is 259808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4	c.207-20T>C		intron_variant	Intron 2 of 14	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.207-20T>C		intron_variant	Intron 2 of 14	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7	c.207-20T>C		intron_variant	Intron 2 of 13	5		ENSP00000393608.3
MUSK	ENST00000189978.10	c.207-20T>C		intron_variant	Intron 2 of 13	5		ENSP00000189978.6
MUSK	ENST00000374439.1	c.-120T>C		upstream_gene_variant		5		ENSP00000363562.2

Frequencies

GnomAD3 genomes AF: 0.0483 AC: 7341 AN: 152014 Hom.: 216 Cov.: 31

Gnomad AFR AF: 0.0320

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0471

Gnomad ASJ AF: 0.0677

Gnomad EAS AF: 0.0892

Gnomad SAS AF: 0.0636

Gnomad FIN AF: 0.0222

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0574

Gnomad OTH AF: 0.0549

GnomAD2 exomes AF: 0.0553 AC: 13427 AN: 242596 AF XY: 0.0566

Gnomad AFR exome AF: 0.0351

Gnomad AMR exome AF: 0.0337

Gnomad ASJ exome AF: 0.0653

Gnomad EAS exome AF: 0.101

Gnomad FIN exome AF: 0.0271

Gnomad NFE exome AF: 0.0595

Gnomad OTH exome AF: 0.0531

GnomAD4 exome AF: 0.0560 AC: 81108 AN: 1449428 Hom.: 2411 Cov.: 30 AF XY: 0.0566 AC XY: 40695 AN XY: 719616

African (AFR) AF: 0.0329 AC: 1091 AN: 33154

American (AMR) AF: 0.0358 AC: 1558 AN: 43506

Ashkenazi Jewish (ASJ) AF: 0.0629 AC: 1616 AN: 25696

East Asian (EAS) AF: 0.0860 AC: 3387 AN: 39394

South Asian (SAS) AF: 0.0644 AC: 5450 AN: 84688

European-Finnish (FIN) AF: 0.0296 AC: 1573 AN: 53086

Middle Eastern (MID) AF: 0.0558 AC: 318 AN: 5698

European-Non Finnish (NFE) AF: 0.0568 AC: 62769 AN: 1104366

Other (OTH) AF: 0.0559 AC: 3346 AN: 59840

GnomAD4 genome AF: 0.0483 AC: 7341 AN: 152132 Hom.: 217 Cov.: 31 AF XY: 0.0473 AC XY: 3517 AN XY: 74384

African (AFR) AF: 0.0319 AC: 1325 AN: 41504

American (AMR) AF: 0.0471 AC: 719 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0677 AC: 235 AN: 3470

East Asian (EAS) AF: 0.0894 AC: 461 AN: 5154

South Asian (SAS) AF: 0.0631 AC: 304 AN: 4820

European-Finnish (FIN) AF: 0.0222 AC: 235 AN: 10606

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0574 AC: 3902 AN: 67988

Other (OTH) AF: 0.0562 AC: 119 AN: 2116

Alfa AF: 0.0503 Hom.: 40

Bravo AF: 0.0496

Asia WGS AF: 0.0670 AC: 231 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

May 27, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.5
DANN	Benign	0.66
PhyloP100		0.40
PromoterAI		-0.0049	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs71501643; hg19: chr9-113449377; COSMIC: COSV51893560; COSMIC: COSV51893560;