rs41313301

Positions:

chr9-105635214-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001079802.2(FKTN):c.1336A>G(p.Asn446Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,614,160 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0085 ( 12 hom., cov: 32)

Exomes 𝑓: 0.011 ( 151 hom. )

Consequence

FKTN
NM_001079802.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:17

Conservation

PhyloP100: 8.89

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:

FKTN (HGNC:):

FKTN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009369671).

BP6

Variant 9-105635214-A-G is Benign according to our data. Variant chr9-105635214-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36138.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=6}. Variant chr9-105635214-A-G is described in Lovd as [Likely_benign]. Variant chr9-105635214-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00853 (1299/152318) while in subpopulation SAS AF= 0.0205 (99/4824). AF 95% confidence interval is 0.0173. There are 12 homozygotes in gnomad4. There are 660 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKTN	NM_001079802.2 linkuse as main transcript	c.1336A>G	p.Asn446Asp	missense_variant	11/11	ENST00000357998.10	NP_001073270.1	O75072-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKTN	ENST00000357998.10 linkuse as main transcript	c.1336A>G	p.Asn446Asp	missense_variant	11/11	5	NM_001079802.2	ENSP00000350687.6		O75072-1

Frequencies

GnomAD3 genomes

AF:

0.00853

AC:

1299

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00183

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0112

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0203

Gnomad FIN

AF:

0.00960

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0111

Gnomad OTH

AF:

0.0120

GnomAD3 exomes

AF:

0.0113

AC:

2841

AN:

251374

Hom.:

AF XY:

0.0126

AC XY:

1714

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00630

Gnomad ASJ exome

AF:

0.0185

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0234

Gnomad FIN exome

AF:

0.00896

Gnomad NFE exome

AF:

0.0127

Gnomad OTH exome

AF:

0.0106

GnomAD4 exome

AF:

0.0106

AC:

15510

AN:

1461842

Hom.:

151

Cov.:

AF XY:

0.0112

AC XY:

8179

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00194

Gnomad4 AMR exome

AF:

0.00711

Gnomad4 ASJ exome

AF:

0.0183

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0239

Gnomad4 FIN exome

AF:

0.00786

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.0109

GnomAD4 genome

AF:

0.00853

AC:

1299

AN:

152318

Hom.:

Cov.:

AF XY:

0.00886

AC XY:

660

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00183

Gnomad4 AMR

AF:

0.0112

Gnomad4 ASJ

AF:

0.0184

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0205

Gnomad4 FIN

AF:

0.00960

Gnomad4 NFE

AF:

0.0111

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.0114

Hom.:

Bravo

AF:

0.00829

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0124

AC:

107

ExAC

AF:

0.0119

AC:

1443

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0123

EpiControl

AF:

0.0136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:17

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:8

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2014	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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 06, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 20, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

Walker-Warburg congenital muscular dystrophy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 26, 2021	- -

Dilated cardiomyopathy 1X

Uncertain:1

Uncertain significance, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiomyopathy

Benign:1

Benign, no assertion criteria provided

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 20, 2015

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 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

Pathogenic

0.59

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

.;D

MetaRNN

Benign

0.0094

T;T

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.6

.;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.012

.;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.58

MPC

0.22

ClinPred

0.020

GERP RS

6.0

Varity_R

0.50

gMVP

0.87

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