rs34787999

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001079802.2(FKTN):c.608G>A(p.Arg203Gln) variant causes a missense change. The variant allele was found at a frequency of 0.285 in 1,613,054 control chromosomes in the GnomAD database, including 69,707 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R203L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.25 ( 5168 hom., cov: 32)

Exomes 𝑓: 0.29 ( 64539 hom. )

Consequence

FKTN
NM_001079802.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24

Conservation

PhyloP100: 4.49

Publications

35 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017285645).

BP6

Variant 9-105604453-G-A is Benign according to our data. Variant chr9-105604453-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079802.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FKTN	NM_001079802.2	MANE Select	c.608G>A	p.Arg203Gln	missense	Exon 6 of 11	NP_001073270.1	O75072-1
FKTN	NM_001351496.2		c.608G>A	p.Arg203Gln	missense	Exon 7 of 12	NP_001338425.1	O75072-1
FKTN	NM_006731.2		c.608G>A	p.Arg203Gln	missense	Exon 5 of 10	NP_006722.2	O75072-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FKTN	ENST00000357998.10	TSL:5 MANE Select	c.608G>A	p.Arg203Gln	missense	Exon 6 of 11	ENSP00000350687.6	O75072-1
FKTN	ENST00000223528.6	TSL:1	c.608G>A	p.Arg203Gln	missense	Exon 5 of 10	ENSP00000223528.2	O75072-1
FKTN	ENST00000602526.1	TSL:1	n.*646G>A		non_coding_transcript_exon	Exon 6 of 11	ENSP00000473347.1	R4GMU0

Frequencies

GnomAD3 genomes

AF:

0.248

AC:

37672

AN:

151994

Hom.:

5162

Cov.:

show subpopulations

Gnomad AFR

AF:

0.157

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.282

Gnomad ASJ

AF:

0.277

Gnomad EAS

AF:

0.0950

Gnomad SAS

AF:

0.106

Gnomad FIN

AF:

0.274

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.312

Gnomad OTH

AF:

0.260

GnomAD2 exomes

AF:

0.248

AC:

62232

AN:

250802

AF XY:

0.243

show subpopulations

Gnomad AFR exome

AF:

0.158

Gnomad AMR exome

AF:

0.277

Gnomad ASJ exome

AF:

0.284

Gnomad EAS exome

AF:

0.0927

Gnomad FIN exome

AF:

0.279

Gnomad NFE exome

AF:

0.308

Gnomad OTH exome

AF:

0.267

GnomAD4 exome

AF:

0.289

AC:

421781

AN:

1460942

Hom.:

64539

Cov.:

AF XY:

0.283

AC XY:

205656

AN XY:

726872

show subpopulations

African (AFR)

AF:

0.150

AC:

5023

AN:

33476

American (AMR)

AF:

0.276

AC:

12336

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.283

AC:

7388

AN:

26130

East Asian (EAS)

AF:

0.102

AC:

4057

AN:

39692

South Asian (SAS)

AF:

0.0980

AC:

8455

AN:

86250

European-Finnish (FIN)

AF:

0.286

AC:

15295

AN:

53412

Middle Eastern (MID)

AF:

0.190

AC:

1093

AN:

5762

European-Non Finnish (NFE)

AF:

0.317

AC:

351720

AN:

1111144

Other (OTH)

AF:

0.272

AC:

16414

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

14749

29499

44248

58998

73747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11240

22480

33720

44960

56200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.248

AC:

37706

AN:

152112

Hom.:

5168

Cov.:

AF XY:

0.243

AC XY:

18054

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.157

AC:

6528

AN:

41510

American (AMR)

AF:

0.283

AC:

4321

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.277

AC:

958

AN:

3462

East Asian (EAS)

AF:

0.0958

AC:

496

AN:

5180

South Asian (SAS)

AF:

0.106

AC:

510

AN:

4826

European-Finnish (FIN)

AF:

0.274

AC:

2886

AN:

10548

Middle Eastern (MID)

AF:

0.184

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.312

AC:

21193

AN:

67988

Other (OTH)

AF:

0.260

AC:

550

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1430

2859

4289

5718

7148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

394

788

1182

1576

1970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.288

Hom.:

21441

Bravo

AF:

0.244

TwinsUK

AF:

0.330

AC:

1223

ALSPAC

AF:

0.323

AC:

1243

ESP6500AA

AF:

0.158

AC:

698

ESP6500EA

AF:

0.319

AC:

2743

ExAC

AF:

0.244

AC:

29681

Asia WGS

AF:

0.122

AC:

424

AN:

3478

EpiCase

AF:

0.304

EpiControl

AF:

0.299

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (10)

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

Dilated cardiomyopathy 1X (2)

not provided (2)

Walker-Warburg congenital muscular dystrophy (2)

Autosomal recessive limb-girdle muscular dystrophy type 2M (1)

Cardiovascular phenotype (1)

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;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 (1)

Muscular dystrophy-dystroglycanopathy (congenital without intellectual disability), type B4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.5

PhyloP100

4.5

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.32

REVEL

Uncertain

0.29

Sift

Benign

0.20

Sift4G

Benign

0.25

Polyphen

0.074

Vest4

0.35

MPC

0.10

ClinPred

0.011

GERP RS

5.4

Varity_R

0.054

gMVP

0.56

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over