Genetic Variant FKTN:c.106-10G>A (chr9-105596588-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001079802.2(FKTN):c.106-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,607,688 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0091 ( 22 hom., cov: 32)

Exomes 𝑓: 0.00086 ( 21 hom. )

Consequence

FKTN
NM_001079802.2 intron

Scores

Splicing: ADA: 0.0001163

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.144

Publications

1 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 (BayesDel_noAF=-0.83).

BP6

Variant 9-105596588-G-A is Benign according to our data. Variant chr9-105596588-G-A is described in ClinVar as Benign. ClinVar VariationId is 93513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00907 (1381/152222) while in subpopulation AFR AF = 0.0319 (1323/41530). AF 95% confidence interval is 0.0304. There are 22 homozygotes in GnomAd4. There are 666 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AR,AD gene

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	Effect	Exon Rank	Protein	UniProt
FKTN	NM_001079802.2	MANE Select	c.106-10G>A	intron	N/A	NP_001073270.1	O75072-1
FKTN	NM_001351496.2		c.106-10G>A	intron	N/A	NP_001338425.1	O75072-1
FKTN	NM_006731.2		c.106-10G>A	intron	N/A	NP_006722.2	O75072-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FKTN	ENST00000357998.10	TSL:5 MANE Select	c.106-10G>A	intron	N/A	ENSP00000350687.6	O75072-1
FKTN	ENST00000223528.6	TSL:1	c.106-10G>A	intron	N/A	ENSP00000223528.2	O75072-1
FKTN	ENST00000602526.1	TSL:1	n.106-10G>A	intron	N/A	ENSP00000473347.1	R4GMU0

Frequencies

GnomAD3 genomes

AF:

0.00909

AC:

1382

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0320

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00234

AC:

587

AN:

251186

AF XY:

0.00172

show subpopulations

Gnomad AFR exome

AF:

0.0326

Gnomad AMR exome

AF:

0.00148

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000860

AC:

1252

AN:

1455466

Hom.:

Cov.:

AF XY:

0.000701

AC XY:

508

AN XY:

724578

show subpopulations

African (AFR)

AF:

0.0318

AC:

1059

AN:

33314

American (AMR)

AF:

0.00141

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39638

South Asian (SAS)

AF:

0.0000465

AC:

AN:

86106

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.000362

AC:

AN:

5520

European-Non Finnish (NFE)

AF:

0.0000172

AC:

AN:

1106606

Other (OTH)

AF:

0.00175

AC:

105

AN:

60138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

107

161

214

268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00907

AC:

1381

AN:

152222

Hom.:

Cov.:

AF XY:

0.00895

AC XY:

666

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0319

AC:

1323

AN:

41530

American (AMR)

AF:

0.00288

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68008

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

125

187

250

312

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00360

Hom.:

Bravo

AF:

0.0104

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

not provided (3)

Walker-Warburg congenital muscular dystrophy (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.5

(source)

DANN

Benign

0.50

PhyloP100

0.14

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.0

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