9-105604245-G-T

Variant names:

• chr9-105604245-G-T
• rs1554752862
• NM_001079802.2:c.400G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001079802.2(FKTN):​c.400G>T​(p.Gly134*) variant causes a stop gained 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G134G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FKTN NM_001079802.2 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.44
• Publications: 0 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-105604245-G-T is Pathogenic according to our data. Variant chr9-105604245-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1724541.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079802.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKTN	NM_001079802.2	MANE Select	c.400G>T	p.Gly134*	stop_gained	Exon 6 of 11	NP_001073270.1	O75072-1
	FKTN	NM_001351496.2		c.400G>T	p.Gly134*	stop_gained	Exon 7 of 12	NP_001338425.1	O75072-1
	FKTN	NM_006731.2		c.400G>T	p.Gly134*	stop_gained	Exon 5 of 10	NP_006722.2	O75072-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKTN	ENST00000357998.10	TSL:5 MANE Select	c.400G>T	p.Gly134*	stop_gained	Exon 6 of 11	ENSP00000350687.6	O75072-1
	FKTN	ENST00000223528.6	TSL:1	c.400G>T	p.Gly134*	stop_gained	Exon 5 of 10	ENSP00000223528.2	O75072-1
	FKTN	ENST00000602526.1	TSL:1	n.*438G>T		non_coding_transcript_exon	Exon 6 of 11	ENSP00000473347.1	R4GMU0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4;C1969040:Autosomal recessive limb-girdle muscular dystrophy type 2M;C2751052:Muscular dystrophy-dystroglycanopathy (congenital without intellectual disability), type B4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		8.4
Vest4		0.84
GERP RS		5.1
Mutation Taster		=1/199	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1554752862; hg19: chr9-108366526; COSMIC: COSV56312267;