rs41277797

Variant names:

• chr9-105601145-C-T
• rs41277797
• NM_001079802.2:c.166C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-105601145-C-T
• chr9-105601145-C-G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_001079802.2(FKTN):​c.166C>T​(p.Arg56Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,558,772 control chromosomes in the GnomAD database, including 484 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. R56H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (50 hom., cov: 32)
  • Exomes 𝑓: 0.022 (434 hom.)
• Consequence: FKTN NM_001079802.2 missense, splice_region
• Scores: Splicing: ADA: 0.9959
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:18
• Conservation: PhyloP100: 2.54
• Publications: 15 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 -8 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 9-105601145-C-T is Benign according to our data. Variant chr9-105601145-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93517.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0204 (3111/152214) while in subpopulation AMR AF = 0.037 (566/15280). AF 95% confidence interval is 0.0345. There are 50 homozygotes in GnomAd4. There are 1508 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 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.166C>T	p.Arg56Cys	missense splice_region	Exon 5 of 11	NP_001073270.1	O75072-1
	FKTN	NM_001351496.2		c.166C>T	p.Arg56Cys	missense splice_region	Exon 6 of 12	NP_001338425.1	O75072-1
	FKTN	NM_006731.2		c.166C>T	p.Arg56Cys	missense splice_region	Exon 4 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.166C>T	p.Arg56Cys	missense splice_region	Exon 5 of 11	ENSP00000350687.6	O75072-1
	FKTN	ENST00000223528.6	TSL:1	c.166C>T	p.Arg56Cys	missense splice_region	Exon 4 of 10	ENSP00000223528.2	O75072-1
	FKTN	ENST00000602526.1	TSL:1	n.*86C>T		splice_region non_coding_transcript_exon	Exon 4 of 11	ENSP00000473347.1	R4GMU0

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3109 AN: 152096 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.00509

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0371

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0291

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0275

Gnomad OTH AF: 0.0259

GnomAD2 exomes AF: 0.0189 AC: 4629 AN: 244618 AF XY: 0.0189

Gnomad AFR exome AF: 0.00432

Gnomad AMR exome AF: 0.0158

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0313

Gnomad NFE exome AF: 0.0269

Gnomad OTH exome AF: 0.0238

GnomAD4 exome AF: 0.0220 AC: 30956 AN: 1406558 Hom.: 434 Cov.: 26 AF XY: 0.0218 AC XY: 15322 AN XY: 702764

African (AFR) AF: 0.00379 AC: 123 AN: 32476

American (AMR) AF: 0.0181 AC: 804 AN: 44334

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 402 AN: 25682

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39346

South Asian (SAS) AF: 0.00319 AC: 270 AN: 84736

European-Finnish (FIN) AF: 0.0308 AC: 1627 AN: 52882

Middle Eastern (MID) AF: 0.0178 AC: 94 AN: 5294

European-Non Finnish (NFE) AF: 0.0248 AC: 26340 AN: 1063392

Other (OTH) AF: 0.0222 AC: 1295 AN: 58416

GnomAD4 genome AF: 0.0204 AC: 3111 AN: 152214 Hom.: 50 Cov.: 32 AF XY: 0.0203 AC XY: 1508 AN XY: 74408

African (AFR) AF: 0.00508 AC: 211 AN: 41562

American (AMR) AF: 0.0370 AC: 566 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4824

European-Finnish (FIN) AF: 0.0291 AC: 308 AN: 10586

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0275 AC: 1867 AN: 68000

Other (OTH) AF: 0.0256 AC: 54 AN: 2108

Alfa AF: 0.0235 Hom.: 191

Bravo AF: 0.0205

TwinsUK AF: 0.0262 AC: 97

ALSPAC AF: 0.0259 AC: 100

ESP6500AA AF: 0.00568 AC: 25

ESP6500EA AF: 0.0283 AC: 243

ExAC AF: 0.0179 AC: 2166

Asia WGS AF: 0.00607 AC: 21 AN: 3472

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	not provided (3)
-	-	2	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 (2)
-	-	2	Walker-Warburg congenital muscular dystrophy (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1X (1)
-	-	1	Muscular dystrophy-dystroglycanopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0066	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.9	L
PhyloP100		2.5
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.41
Sift	Benign	0.047	D
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.33
MPC		0.21
ClinPred		0.024	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.56
Mutation Taster		=80/20	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.010		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: rs41277797; hg19: chr9-108363426;