dbSNP rs587780334: FKRP:p.Glu343Lys (chr19-46756477-G-A) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5

The NM_024301.5(FKRP):c.1027G>A(p.Glu343Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000732 in 1,366,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E343Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.58

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-46756477-G-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.927

PP5

Variant 19-46756477-G-A is Pathogenic according to our data. Variant chr19-46756477-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5 link	c.1027G>A	p.Glu343Lys	missense_variant	Exon 4 of 4	ENST00000318584.10	NP_077277.1	Q9H9S5A0A024R0R7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FKRP	ENST00000318584.10 link	c.1027G>A	p.Glu343Lys	missense_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4	Q9H9S5
FKRP	ENST00000391909.7 link	c.1027G>A	p.Glu343Lys	missense_variant	Exon 4 of 4	2		ENSP00000375776.2	Q9H9S5
FKRP	ENST00000597339.5 link	n.247-5356G>A		intron_variant	Intron 3 of 3	5
FKRP	ENST00000600646.5 link	n.247+7812G>A		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.32e-7

AC:

AN:

1366974

Hom.:

Cov.:

AF XY:

0.00000149

AC XY:

AN XY:

670262

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.35e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.1

M;M

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.3

D;D

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.73

MutPred

0.45

Gain of MoRF binding (P = 0.0064);Gain of MoRF binding (P = 0.0064);

MVP

0.96

MPC

1.7

ClinPred

1.0

GERP RS

4.4

Varity_R

0.97

gMVP

0.98

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over