rs34787999

Positions:

chr9-105604453-G-A

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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:22

Conservation

PhyloP100: 4.49

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 93522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-105604453-G-A is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKTN	NM_001079802.2 linkuse as main transcript	c.608G>A	p.Arg203Gln	missense_variant	6/11	ENST00000357998.10	NP_001073270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKTN	ENST00000357998.10 linkuse as main transcript	c.608G>A	p.Arg203Gln	missense_variant	6/11	5	NM_001079802.2	ENSP00000350687	P1	O75072-1

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

GnomAD3 exomes

AF:

0.248

AC:

62232

AN:

250802

Hom.:

8674

AF XY:

0.243

AC XY:

32987

AN XY:

135578

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 SAS exome

AF:

0.0965

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

Gnomad4 AFR exome

AF:

0.150

Gnomad4 AMR exome

AF:

0.276

Gnomad4 ASJ exome

AF:

0.283

Gnomad4 EAS exome

AF:

0.102

Gnomad4 SAS exome

AF:

0.0980

Gnomad4 FIN exome

AF:

0.286

Gnomad4 NFE exome

AF:

0.317

Gnomad4 OTH exome

AF:

0.272

GnomAD4 genome

AF:

0.248

AC:

37706

AN:

152112

Hom.:

5168

Cov.:

AF XY:

0.243

AC XY:

18054

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.157

Gnomad4 AMR

AF:

0.283

Gnomad4 ASJ

AF:

0.277

Gnomad4 EAS

AF:

0.0958

Gnomad4 SAS

AF:

0.106

Gnomad4 FIN

AF:

0.274

Gnomad4 NFE

AF:

0.312

Gnomad4 OTH

AF:

0.260

Alfa

AF:

0.293

Hom.:

10552

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

Significance: Benign/Likely benign

Submissions summary: Benign:22

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Arg203Gln in exon 6 of FKTN: This variant is not expected to have clinical sig nificance because it has been identified in 31.9% (2743/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs34787999). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 08, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Dilated cardiomyopathy 1X

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Walker-Warburg congenital muscular dystrophy

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 28, 2017

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 15, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Autosomal recessive limb-girdle muscular dystrophy type 2M

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;T;.;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.77

.;T;.;T

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.5

L;L;L;L

MutationTaster

Benign

0.078

P;P;P

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.32

.;N;.;N

REVEL

Uncertain

0.29

Sift

Benign

0.20

.;T;.;T

Sift4G

Benign

0.25

T;T;T;T

Polyphen

0.074

B;B;.;.

Vest4

0.35

MPC

0.10

ClinPred

0.011

GERP RS

5.4

Varity_R

0.054

gMVP

0.56

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over