rs141918432

Variant names:

• chr9-105635175-A-G
• rs141918432
• NM_001079802.2:c.1297A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-105635175-A-G
• chr9-105635175-A-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001079802.2(FKTN):​c.1297A>G​(p.Thr433Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,614,198 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T433M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (10 hom.)
• Consequence: FKTN NM_001079802.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 2.49
• Publications: 14 publications found

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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• 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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007936269).
• BP6: Variant 9-105635175-A-G is Benign according to our data. Variant chr9-105635175-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36137.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS2: High Homozygotes in GnomAdExome4 at 10 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKTN	NM_001079802.2	c.1297A>G	p.Thr433Ala	missense_variant	Exon 11 of 11	ENST00000357998.10	NP_001073270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKTN	ENST00000357998.10	c.1297A>G	p.Thr433Ala	missense_variant	Exon 11 of 11	5	NM_001079802.2	ENSP00000350687.6

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152206 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00688

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00203 AC: 510 AN: 251428 AF XY: 0.00211

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00753

Gnomad NFE exome AF: 0.00283

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00262 AC: 3830 AN: 1461874 Hom.: 10 Cov.: 32 AF XY: 0.00256 AC XY: 1861 AN XY: 727236

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00717 AC: 383 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00296 AC: 3288 AN: 1111996

Other (OTH) AF: 0.00219 AC: 132 AN: 60394

GnomAD4 genome AF: 0.00217 AC: 330 AN: 152324 Hom.: 1 Cov.: 32 AF XY: 0.00240 AC XY: 179 AN XY: 74496

African (AFR) AF: 0.000409 AC: 17 AN: 41586

American (AMR) AF: 0.000458 AC: 7 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00688 AC: 73 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00335 AC: 228 AN: 68014

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00239 Hom.: 1

Bravo AF: 0.00132

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00183 AC: 222

EpiCase AF: 0.00267

EpiControl AF: 0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Dec 10, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FKTN c.1297A>G (p.Thr433Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 1614198 control chromosomes, predominantly at a frequency of 0.003 within the Non-Finnish European subpopulation in the gnomAD database, including 8 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in FKTN causing Cardiomyopathy (0.0026 vs 0.005), allowing no conclusion about variant significance. c.1297A>G has been observed in individual(s) affected with Cardiomyopathy (Jaaskelainen_2019) without evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with other pathogenic variant(s) have been reported (MYH7 c.3158G>A, p.Arg1053Gln; MYBPC3 c.927-2A>G; MYBPC3 c.2373dup, p.Trp792fs; MYBPC3 c.3181C>T, p.Gln1061Ter), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30775854). ClinVar contains an entry for this variant (Variation ID: 36137). Based on the evidence outlined above, the variant was classified as likely benign. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Apr 29, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 10, 2019

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FKTN: BP4, BS1, BS2 -

Walker-Warburg congenital muscular dystrophy Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1X Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Ventricular tachycardia;C0878544:Cardiomyopathy Benign:1

Jan 10, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

May 09, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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	0.071
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.53	.;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.0079	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		2.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.5	.;N
REVEL	Benign	0.074
Sift	Benign	0.25	.;T
Sift4G	Benign	0.33	T;T
Polyphen		0.0030	B;B
Vest4		0.021
MVP		0.24
MPC		0.081
ClinPred		0.012	T
GERP RS		3.7
Varity_R		0.046
gMVP		0.39
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs141918432; hg19: chr9-108397456;