rs1448279636

Variant names:

• chr9-105604402-A-G
• rs1448279636
• NM_001079802.2:c.557A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-105604402-A-G
• chr9-105604402-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001079802.2(FKTN):​c.557A>G​(p.His186Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FKTN NM_001079802.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 7.87

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKTN	NM_001079802.2	c.557A>G	p.His186Arg	missense_variant	Exon 6 of 11	ENST00000357998.10	NP_001073270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKTN	ENST00000357998.10	c.557A>G	p.His186Arg	missense_variant	Exon 6 of 11	5	NM_001079802.2	ENSP00000350687.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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 Pathogenic:1

Jun 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Jun 14, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FKTN c.557A>G (p.His186Arg) results in a non-conservative amino acid change located in the Ribitol-5-phosphate transferase FKTN, N-terminal domain (IPR045587) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251212 control chromosomes. c.557A>G has been reported in the literature in the homozygous state in an individual affected with classic Walker-Warburg Syndrome (Manzini_2008). These data indicate that the variant may be associated with disease. At least one functional study found that the variant protein was retained in the ER as opposed to localizing to the golgi, but that it also retained the activity responsible for -DG glycosylation similar to that of the WT protein (Tachikawa_2012). The following publications have been ascertained in the context of this evaluation (PMID: 18752264, 22275357). ClinVar contains an entry for this variant (Variation ID: 554414). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

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

Oct 17, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Sep 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H186R variant (also known as c.557A>G), located in coding exon 4 of the FKTN gene, results from an A to G substitution at nucleotide position 557. The histidine at codon 186 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported as homozygous in an individual with Walker-Warburg syndrome (Manzini MC et al. Hum Mutat, 2008 Nov;29:E231-41). In multiple assays testing FKTN function, this variant showed functionally abnormal and functionally normal results (Tachikawa M et al. J Biol Chem, 2012 Mar;287:8398-406). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;D;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	.;D;.;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.3	M;M;M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.4	.;D;.;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.015	.;D;.;D
Sift4G	Uncertain	0.038	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.96
MutPred		0.92		Gain of MoRF binding (P = 0.0037);Gain of MoRF binding (P = 0.0037);Gain of MoRF binding (P = 0.0037);Gain of MoRF binding (P = 0.0037);
MVP		0.91
MPC		0.45
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.48
gMVP		0.96

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

Other links and lift over

dbSNP: rs1448279636; hg19: chr9-108366683;