9-105606576-G-T

Variant names:

• chr9-105606576-G-T
• rs1554754182
• NM_001079802.2:c.648-1243G>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001079802.2(FKTN):​c.648-1243G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FKTN NM_001079802.2 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.100

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-105606576-G-T is Pathogenic according to our data. Variant chr9-105606576-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-105606576-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKTN	NM_001079802.2	c.648-1243G>T		intron_variant	Intron 6 of 10	ENST00000357998.10	NP_001073270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKTN	ENST00000357998.10	c.648-1243G>T		intron_variant	Intron 6 of 10	5	NM_001079802.2	ENSP00000350687.6

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

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;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1X Pathogenic:1

Mar 24, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 24, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FKTN c.648-1243G>T involves the alteration of a non-conserved nucleotide resulting in an intronic change. Several computational tools predict a significant impact on normal splicing: Two predict the variant strengthens a cryptic 5' donor site. One predicts the variant creates a cryptic 5' donor site. In addition, this variant is predicted to create a pseudoexon between exon 5 and exon 6 resulting in a frameshift and a premature stop codon (Kobayashi_2017). Another study showed patients with parental origins of this variant and direct sequencing of RNA showed the 64bp pseudogene insertion (Lim_2010). The variant was absent in 192 control chromosomes (gnomAD and publication data). c.648-1243G>T has been reported in the literature as a compound heterozygous genotype with a pathogenic variant in multiple individuals affected with Fukuyama Congenital Muscular Dystrophy (Example: Suzuki_2022, Kobayashi_2017, Lim_2010 etc.) and was shown to segregate with disease (Kobayashi_2017). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite this variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Walker-Warburg congenital muscular dystrophy Pathogenic:1

Feb 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 6 of the FKTN gene. It does not directly change the encoded amino acid sequence of the FKTN protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with congenital muscular dystrophy (PMID: 20620061, 28680109). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.647+2084G>T. ClinVar contains an entry for this variant (Variation ID: 496331). Studies have shown that this variant results in insertion of a pseudoexon and introduces a premature termination codon (PMID: 20620061, 28680109). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	18
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554754182; hg19: chr9-108368857;