rs193922689

Variant names:

• chr9-105601141-A-G
• rs193922689
• NM_001079802.2:c.166-4A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001079802.2(FKTN):​c.166-4A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00084 in 1,553,096 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00080 (2 hom.)
• Consequence: FKTN NM_001079802.2 splice_region, intron
• Scores: Splicing: ADA: 0.9986
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:4
• Conservation: PhyloP100: 3.96
• Publications: 2 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: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.166-4A>G		splice_region intron	N/A	NP_001073270.1	O75072-1
	FKTN	NM_001351496.2		c.166-4A>G		splice_region intron	N/A	NP_001338425.1	O75072-1
	FKTN	NM_006731.2		c.166-4A>G		splice_region intron	N/A	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.166-4A>G		splice_region intron	N/A	ENSP00000350687.6	O75072-1
	FKTN	ENST00000223528.6	TSL:1	c.166-4A>G		splice_region intron	N/A	ENSP00000223528.2	O75072-1
	FKTN	ENST00000602526.1	TSL:1	n.*86-4A>G		splice_region intron	N/A	ENSP00000473347.1	R4GMU0

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152196 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000761 AC: 185 AN: 243196 AF XY: 0.000851

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.0000588

Gnomad ASJ exome AF: 0.000607

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00297

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000802 AC: 1124 AN: 1400782 Hom.: 2 Cov.: 25 AF XY: 0.000873 AC XY: 611 AN XY: 700228

African (AFR) AF: 0.0000619 AC: 2 AN: 32330

American (AMR) AF: 0.0000677 AC: 3 AN: 44286

Ashkenazi Jewish (ASJ) AF: 0.000703 AC: 18 AN: 25614

East Asian (EAS) AF: 0.00 AC: 0 AN: 39314

South Asian (SAS) AF: 0.00 AC: 0 AN: 84464

European-Finnish (FIN) AF: 0.00291 AC: 154 AN: 52860

Middle Eastern (MID) AF: 0.000192 AC: 1 AN: 5200

European-Non Finnish (NFE) AF: 0.000850 AC: 900 AN: 1058524

Other (OTH) AF: 0.000791 AC: 46 AN: 58190

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152314 Hom.: 2 Cov.: 33 AF XY: 0.00133 AC XY: 99 AN XY: 74484

African (AFR) AF: 0.000120 AC: 5 AN: 41580

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00480 AC: 51 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00174 AC: 118 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00156 Hom.: 0

Bravo AF: 0.000552

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	not provided (5)
-	2	-	Cardiovascular phenotype (2)
-	1	1	not specified (2)
-	1	-	Dilated cardiomyopathy 1X (1)
-	-	1	FKTN-related disorder (1)
-	1	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 (1)
-	1	-	Myopathy caused by variation in FKTN (1)
-	-	1	Walker-Warburg congenital muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Benign	0.96
PhyloP100		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.81
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.85		Position offset: 1

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

Other links and lift over

dbSNP: rs193922689; hg19: chr9-108363422;