9-105601146-G-A

Variant names:

• chr9-105601146-G-A
• rs146951171
• NM_001079802.2:c.167G>A

Variant summary

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

The NM_001351499.2(FKTN):​c.-348G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,566,964 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: FKTN NM_001351499.2 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.004493
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:13
• Conservation: PhyloP100: 2.31
• Publications: 3 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008233577).
• BP6: Variant 9-105601146-G-A is Benign according to our data. Variant chr9-105601146-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93518.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001351499.2. 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.167G>A	p.Arg56His	missense splice_region	Exon 5 of 11	NP_001073270.1	O75072-1
	FKTN	NM_001351499.2		c.-348G>A		5_prime_UTR_premature_start_codon_gain	Exon 6 of 13	NP_001338428.1
	FKTN	NM_001351500.2		c.-348G>A		5_prime_UTR_premature_start_codon_gain	Exon 5 of 12	NP_001338429.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKTN	ENST00000357998.10	TSL:5 MANE Select	c.167G>A	p.Arg56His	missense splice_region	Exon 5 of 11	ENSP00000350687.6	O75072-1
	FKTN	ENST00000223528.6	TSL:1	c.167G>A	p.Arg56His	missense splice_region	Exon 4 of 10	ENSP00000223528.2	O75072-1
	FKTN	ENST00000602526.1	TSL:1	n.*87G>A		splice_region non_coding_transcript_exon	Exon 4 of 11	ENSP00000473347.1	R4GMU0

Frequencies

GnomAD3 genomes AF: 0.00203 AC: 308 AN: 152086 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00705

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000526 AC: 129 AN: 245444 AF XY: 0.000399

Gnomad AFR exome AF: 0.00703

Gnomad AMR exome AF: 0.000410

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000182 AC: 257 AN: 1414760 Hom.: 2 Cov.: 26 AF XY: 0.000163 AC XY: 115 AN XY: 706562

African (AFR) AF: 0.00616 AC: 201 AN: 32608

American (AMR) AF: 0.000450 AC: 20 AN: 44430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25742

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39382

South Asian (SAS) AF: 0.0000589 AC: 5 AN: 84900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52958

Middle Eastern (MID) AF: 0.000750 AC: 4 AN: 5332

European-Non Finnish (NFE) AF: 0.00000654 AC: 7 AN: 1070708

Other (OTH) AF: 0.000307 AC: 18 AN: 58700

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152204 Hom.: 3 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74422

African (AFR) AF: 0.00703 AC: 292 AN: 41528

American (AMR) AF: 0.000589 AC: 9 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.000662 Hom.: 0

Bravo AF: 0.00193

ESP6500AA AF: 0.00614 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000667 AC: 81

Asia WGS AF: 0.00116 AC: 4 AN: 3472

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.3
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.16
Sift	Benign	0.36	T
Sift4G	Benign	0.66	T
Polyphen		0.0060	B
Vest4		0.17
MVP		0.80
MPC		0.10
ClinPred		0.014	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.040
gMVP		0.39
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0045
dbscSNV1_RF	Benign	0.15
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: rs146951171; hg19: chr9-108363427; COSMIC: COSV56308330; COSMIC: COSV56308330;