rs34006675

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001079802.2(FKTN):c.373G>A(p.Gly125Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,612,204 control chromosomes in the GnomAD database, including 389 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. G125A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.031 ( 165 hom., cov: 32)

Exomes 𝑓: 0.012 ( 224 hom. )

Consequence

FKTN
NM_001079802.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:12

Conservation

PhyloP100: 1.68

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 -16 ACMG points.

BP6

Variant 9-105604218-G-A is Benign according to our data. Variant chr9-105604218-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-105604218-G-A is described in Lovd as [Benign]. Variant chr9-105604218-G-A is described in Lovd as [Pathogenic]. Variant chr9-105604218-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0855 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKTN	NM_001079802.2 linkuse as main transcript	c.373G>A	p.Gly125Ser	missense_variant	6/11	ENST00000357998.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKTN	ENST00000357998.10 linkuse as main transcript	c.373G>A	p.Gly125Ser	missense_variant	6/11	5	NM_001079802.2	P1	O75072-1

Frequencies

GnomAD3 genomes

AF:

0.0315

AC:

4789

AN:

152122

Hom.:

164

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0879

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00706

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0111

Gnomad OTH

AF:

0.0258

GnomAD3 exomes

AF:

0.0138

AC:

3450

AN:

249614

Hom.:

AF XY:

0.0122

AC XY:

1653

AN XY:

135106

show subpopulations

Gnomad AFR exome

AF:

0.0905

Gnomad AMR exome

AF:

0.0111

Gnomad ASJ exome

AF:

0.00625

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00281

Gnomad FIN exome

AF:

0.00702

Gnomad NFE exome

AF:

0.0109

Gnomad OTH exome

AF:

0.0118

GnomAD4 exome

AF:

0.0117

AC:

17068

AN:

1459964

Hom.:

224

Cov.:

AF XY:

0.0111

AC XY:

8073

AN XY:

726308

show subpopulations

Gnomad4 AFR exome

AF:

0.0917

Gnomad4 AMR exome

AF:

0.0108

Gnomad4 ASJ exome

AF:

0.00612

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00315

Gnomad4 FIN exome

AF:

0.00696

Gnomad4 NFE exome

AF:

0.0105

Gnomad4 OTH exome

AF:

0.0145

GnomAD4 genome

AF:

0.0315

AC:

4795

AN:

152240

Hom.:

165

Cov.:

AF XY:

0.0299

AC XY:

2222

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0879

Gnomad4 AMR

AF:

0.0144

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.00706

Gnomad4 NFE

AF:

0.0111

Gnomad4 OTH

AF:

0.0255

Alfa

AF:

0.0156

Hom.:

Bravo

AF:

0.0348

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.0117

AC:

ESP6500AA

AF:

0.0867

AC:

382

ESP6500EA

AF:

0.0114

AC:

ExAC

AF:

0.0153

AC:

1862

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.0104

EpiControl

AF:

0.0101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 06, 2012	- -
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	Genetic Services Laboratory, University of Chicago	Apr 16, 2013	- -

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

Uncertain:1Benign:1

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. -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jan 12, 2011	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2023	- -

Walker-Warburg congenital muscular dystrophy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 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

0.074

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.18

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.092

T;T;.;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.77

MetaRNN

Benign

0.0021

T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.4

L;L;L;L

MutationTaster

Benign

0.56

N;N;N

PrimateAI

Benign

0.35

Sift4G

Benign

0.65

T;T;T;T

Polyphen

0.047

B;B;.;.

Vest4

0.23

MPC

0.082

ClinPred

0.019

GERP RS

1.7

Varity_R

0.057

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.21

Position offset: 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