rs41313301

Variant names:

• chr9-105635214-A-G
• rs41313301
• NM_001079802.2:c.1336A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001079802.2(FKTN):​c.1336A>G​(p.Asn446Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,614,160 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N446S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0085 (12 hom., cov: 32)
  • Exomes 𝑓: 0.011 (151 hom.)
• Consequence: FKTN NM_001079802.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:19
• Conservation: PhyloP100: 8.89
• Publications: 26 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009369671).
• BP6: Variant 9-105635214-A-G is Benign according to our data. Variant chr9-105635214-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36138.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00853 (1299/152318) while in subpopulation SAS AF = 0.0205 (99/4824). AF 95% confidence interval is 0.0173. There are 12 homozygotes in GnomAd4. There are 660 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.1336A>G	p.Asn446Asp	missense	Exon 11 of 11	NP_001073270.1	O75072-1
	FKTN	NM_001351496.2		c.1336A>G	p.Asn446Asp	missense	Exon 12 of 12	NP_001338425.1	O75072-1
	FKTN	NM_006731.2		c.1336A>G	p.Asn446Asp	missense	Exon 10 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.1336A>G	p.Asn446Asp	missense	Exon 11 of 11	ENSP00000350687.6	O75072-1
	FKTN	ENST00000223528.6	TSL:1	c.1336A>G	p.Asn446Asp	missense	Exon 10 of 10	ENSP00000223528.2	O75072-1
	FKTN	ENST00000602526.1	TSL:1	n.*1374A>G		non_coding_transcript_exon	Exon 11 of 11	ENSP00000473347.1	R4GMU0

Frequencies

GnomAD3 genomes AF: 0.00853 AC: 1299 AN: 152200 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.00960

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0113 AC: 2841 AN: 251374 AF XY: 0.0126

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00630

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00896

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0106 AC: 15510 AN: 1461842 Hom.: 151 Cov.: 32 AF XY: 0.0112 AC XY: 8179 AN XY: 727222

African (AFR) AF: 0.00194 AC: 65 AN: 33480

American (AMR) AF: 0.00711 AC: 318 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 477 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0239 AC: 2060 AN: 86256

European-Finnish (FIN) AF: 0.00786 AC: 420 AN: 53420

Middle Eastern (MID) AF: 0.0232 AC: 134 AN: 5768

European-Non Finnish (NFE) AF: 0.0102 AC: 11376 AN: 1111966

Other (OTH) AF: 0.0109 AC: 657 AN: 60394

GnomAD4 genome AF: 0.00853 AC: 1299 AN: 152318 Hom.: 12 Cov.: 32 AF XY: 0.00886 AC XY: 660 AN XY: 74484

African (AFR) AF: 0.00183 AC: 76 AN: 41572

American (AMR) AF: 0.0112 AC: 171 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0205 AC: 99 AN: 4824

European-Finnish (FIN) AF: 0.00960 AC: 102 AN: 10628

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0111 AC: 754 AN: 68032

Other (OTH) AF: 0.0118 AC: 25 AN: 2110

Alfa AF: 0.0110 Hom.: 56

Bravo AF: 0.00829

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0124 AC: 107

ExAC AF: 0.0119 AC: 1443

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0123

EpiControl AF: 0.0136

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	4	not provided (4)
-	-	2	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 (2)
-	-	2	Walker-Warburg congenital muscular dystrophy (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1X (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		8.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.012	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.58
MPC		0.22
ClinPred		0.020	T
GERP RS		6.0
Varity_R		0.50
gMVP		0.87
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs41313301; hg19: chr9-108397495; COSMIC: COSV107302126;