rs1554766855

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM4PP3PP5

The NM_001079802.2(FKTN):c.1215_1226delAGACATGAAGGT(p.Asp406_Val409del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V405V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

FKTN
NM_001079802.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:4

Conservation

PhyloP100: 9.54

Publications

0 publications found

Variant links:

Genes affected

FKTN (HGNC:3622): (fukutin) The protein encoded by this gene is a putative transmembrane protein that is localized to the cis-Golgi compartment, where it may be involved in the glycosylation of alpha-dystroglycan in skeletal muscle. The encoded protein is thought to be a glycosyltransferase and could play a role in brain development. Defects in this gene are a cause of Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), limb-girdle muscular dystrophy type 2M (LGMD2M), and dilated cardiomyopathy type 1X (CMD1X). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2010]

FKTN Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy type 2M
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
myopathy caused by variation in FKTN
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
congenital muscular dystrophy without intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
muscle-eye-brain disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
muscular dystrophy-dystroglycanopathy, type A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy 1X
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

FKTN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001079802.2.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant 9-105635090-TGTAGACATGAAG-T is Pathogenic according to our data. Variant chr9-105635090-TGTAGACATGAAG-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 431957.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKTN	NM_001079802.2 link	c.1215_1226delAGACATGAAGGT	p.Asp406_Val409del	disruptive_inframe_deletion	Exon 11 of 11	ENST00000357998.10	NP_001073270.1	O75072-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKTN	ENST00000357998.10 link	c.1215_1226delAGACATGAAGGT	p.Asp406_Val409del	disruptive_inframe_deletion	Exon 11 of 11	5	NM_001079802.2	ENSP00000350687.6		O75072-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251360

AF XY:

0.00000736

show subpopulations

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461856

Hom.:

AF XY:

0.00000275

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111984

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4

Pathogenic:1Uncertain:1

Oct 01, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PM4, PP4, PP5 -

Jan 06, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Walker-Warburg congenital muscular dystrophy

Uncertain:2

Aug 13, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.1215_1226del, results in the deletion of 4 amino acid(s) of the FKTN protein (p.Asp406_Val409del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Walker-Warburg syndrome (PMID: 20961758). ClinVar contains an entry for this variant (Variation ID: 431957). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Aug 18, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4;C1969024:Dilated cardiomyopathy 1X;C1969040:Autosomal recessive limb-girdle muscular dystrophy type 2M;C2751052:Muscular dystrophy-dystroglycanopathy (congenital without intellectual disability), type B4

Pathogenic:1

Feb 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1X

Pathogenic:1

Jul 11, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Jun 23, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A variant of uncertain significance has been identified in the FKTN gene. The c.1215_1226del12 variant has been reported in a female infant of Greek and Croatian ancestry, who was diagnosed with Walker-Warburg syndrome and also harbored the R47X variant in the FKTN gene and the R95C variant in the FKRP gene (Yis et al., 2011). Parental testing revealed that the c.1215_1226del12 variant in the FKTN gene was maternally inherited, and the R47X variant in the FKTN gene reportedly occurred de novo in this infant (Yis et al., 2011); although parental identity testing and/or additional studies to confirm whether the two FKTN variants were on the same or opposite alleles were not reported. The c.1215_1226del12 variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.1215_1226del12 variant results in the in-frame deletion of four amino acids, from aspartic acid (D) 406 to valine (V) 409, denoted p.Asp406_Val409del. However, no other in-frame deletions have been reported in HGMD in association with FKTN-related disorders (Stenson et al., 2014). Furthermore, in the absence of functional expression studies, the physiological consequence of this variant cannot be precisely determined. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.5

Mutation Taster

=13/187

disease causing

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over