rs764641619

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_024301.5(FKRP):c.731G>A(p.Arg244His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,439,292 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R244L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:11B:1

Conservation

PhyloP100: 0.0810

Publications

1 publications found

Variant links:

Genes affected

FKRP (HGNC:17997): (fukutin related protein) This gene encodes a protein which is targeted to the medial Golgi apparatus and is necessary for posttranslational modification of dystroglycan. Mutations in this gene have been associated with congenital muscular dystrophy, cognitive disability, and cerebellar cysts. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Oct 2008]

FKRP Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy type 2I
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics
muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Genomics England PanelApp, Ambry Genetics
muscular dystrophy-dystroglycanopathy type B5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health
myopathy caused by variation in FKRP
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
congenital muscular dystrophy with cerebellar involvement
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital muscular dystrophy with intellectual disability
Inheritance: AR 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

FKRP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 46 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.8498 (below the threshold of 3.09). Trascript score misZ: -2.4986 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive limb-girdle muscular dystrophy type 2I, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5, congenital muscular dystrophy with intellectual disability, muscular dystrophy-dystroglycanopathy, type A, muscle-eye-brain disease, congenital muscular dystrophy with cerebellar involvement, myopathy caused by variation in FKRP, muscular dystrophy-dystroglycanopathy type B5, congenital muscular dystrophy without intellectual disability.

BP4

Computational evidence support a benign effect (MetaRNN=0.20556077).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024301.5. 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
	FKRP	NM_024301.5	MANE Select	c.731G>A	p.Arg244His	missense	Exon 4 of 4	NP_077277.1	Q9H9S5
	FKRP	NM_001039885.3		c.731G>A	p.Arg244His	missense	Exon 4 of 4	NP_001034974.1	Q9H9S5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FKRP	ENST00000318584.10	TSL:1 MANE Select	c.731G>A	p.Arg244His	missense	Exon 4 of 4	ENSP00000326570.4	Q9H9S5
FKRP	ENST00000391909.7	TSL:2	c.731G>A	p.Arg244His	missense	Exon 4 of 4	ENSP00000375776.2	Q9H9S5
FKRP	ENST00000908841.1		c.731G>A	p.Arg244His	missense	Exon 3 of 3	ENSP00000578900.1

Frequencies

GnomAD3 genomes

AF:

0.000258

AC:

AN:

151140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00106

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000295

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000266

Gnomad OTH

AF:

0.000962

GnomAD2 exomes

AF:

0.000348

AC:

AN:

57478

AF XY:

0.000294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000870

Gnomad ASJ exome

AF:

0.000212

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000403

Gnomad OTH exome

AF:

0.000558

GnomAD4 exome

AF:

0.000111

AC:

143

AN:

1288044

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

633324

show subpopulations

African (AFR)

AF:

0.0000401

AC:

AN:

24948

American (AMR)

AF:

0.000848

AC:

AN:

20040

Ashkenazi Jewish (ASJ)

AF:

0.0000944

AC:

AN:

21182

East Asian (EAS)

AF:

0.00

AC:

AN:

27840

South Asian (SAS)

AF:

0.0000145

AC:

AN:

68740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32582

Middle Eastern (MID)

AF:

0.000193

AC:

AN:

5184

European-Non Finnish (NFE)

AF:

0.000102

AC:

106

AN:

1034502

Other (OTH)

AF:

0.000283

AC:

AN:

53026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000258

AC:

AN:

151248

Hom.:

Cov.:

AF XY:

0.000203

AC XY:

AN XY:

73914

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41430

American (AMR)

AF:

0.00105

AC:

AN:

15174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000295

AC:

AN:

10162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000266

AC:

AN:

67718

Other (OTH)

AF:

0.000951

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000325

ExAC

AF:

0.0000299

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Autosomal recessive limb-girdle muscular dystrophy type 2I (2)

Cardiovascular phenotype (2)

not specified (2)

Autosomal recessive limb-girdle muscular dystrophy type 2I;C1847759:Muscular dystrophy-dystroglycanopathy type B5;C3150413:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 (1)

Walker-Warburg congenital muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Uncertain

0.010

CADD

Benign

8.5

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.26

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.52

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.21

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

0.34

PhyloP100

0.081

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.60

Sift

Benign

0.21

Sift4G

Benign

0.29

Polyphen

0.0010

Vest4

0.054

MutPred

0.70

Loss of solvent accessibility (P = 0.0128)

MVP

0.77

MPC

0.78

ClinPred

0.015

GERP RS

0.98

Varity_R

0.060

gMVP

0.68

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over