Genetic Variant FKRP:c.-34C>T (chr19-46755417-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024301.5(FKRP):c.-34C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,582,586 control chromosomes in the GnomAD database, including 43,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2881 hom., cov: 33)

Exomes 𝑓: 0.23 ( 40135 hom. )

Consequence

FKRP
NM_024301.5 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.15

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 19-46755417-C-T is Benign according to our data. Variant chr19-46755417-C-T is described in ClinVar as [Benign]. Clinvar id is 96104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755417-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5 link	c.-34C>T		5_prime_UTR_variant	Exon 4 of 4	ENST00000318584.10	NP_077277.1	Q9H9S5A0A024R0R7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584 link	c.-34C>T		5_prime_UTR_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4		Q9H9S5

Frequencies

GnomAD3 genomes

AF:

0.173

AC:

26349

AN:

152108

Hom.:

2878

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0637

Gnomad AMI

AF:

0.274

Gnomad AMR

AF:

0.139

Gnomad ASJ

AF:

0.268

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.175

Gnomad FIN

AF:

0.210

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.247

Gnomad OTH

AF:

0.203

GnomAD3 exomes

AF:

0.187

AC:

38453

AN:

206048

Hom.:

4343

AF XY:

0.194

AC XY:

22172

AN XY:

114158

show subpopulations

Gnomad AFR exome

AF:

0.0581

Gnomad AMR exome

AF:

0.103

Gnomad ASJ exome

AF:

0.261

Gnomad EAS exome

AF:

0.000551

Gnomad SAS exome

AF:

0.195

Gnomad FIN exome

AF:

0.211

Gnomad NFE exome

AF:

0.251

Gnomad OTH exome

AF:

0.210

GnomAD4 exome

AF:

0.229

AC:

327436

AN:

1430360

Hom.:

40135

Cov.:

AF XY:

0.229

AC XY:

162548

AN XY:

710476

show subpopulations

Gnomad4 AFR exome

AF:

0.0568

Gnomad4 AMR exome

AF:

0.109

Gnomad4 ASJ exome

AF:

0.258

Gnomad4 EAS exome

AF:

0.000569

Gnomad4 SAS exome

AF:

0.195

Gnomad4 FIN exome

AF:

0.214

Gnomad4 NFE exome

AF:

0.250

Gnomad4 OTH exome

AF:

0.208

GnomAD4 genome

AF:

0.173

AC:

26351

AN:

152226

Hom.:

2881

Cov.:

AF XY:

0.171

AC XY:

12729

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0635

Gnomad4 AMR

AF:

0.139

Gnomad4 ASJ

AF:

0.268

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.177

Gnomad4 FIN

AF:

0.210

Gnomad4 NFE

AF:

0.247

Gnomad4 OTH

AF:

0.200

Alfa

AF:

0.218

Hom.:

1102

Bravo

AF:

0.163

Asia WGS

AF:

0.0690

AC:

240

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 21, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 15, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2I

Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Muscular dystrophy-dystroglycanopathy type B5

Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

9.0

DANN

Benign

0.73

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over