rs140084192

Positions:

chr19-46756056-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7

The NM_024301.5(FKRP):c.606G>A(p.Leu202=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,576,776 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00066 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

FKRP
NM_024301.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -0.124

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 19-46756056-G-A is Benign according to our data. Variant chr19-46756056-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96113.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr19-46756056-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.124 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKRP	NM_024301.5 linkuse as main transcript	c.606G>A	p.Leu202=	synonymous_variant	4/4	ENST00000318584.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
FKRP	ENST00000318584.10 linkuse as main transcript	c.606G>A	p.Leu202=	synonymous_variant	4/4	1	NM_024301.5	P1
FKRP	ENST00000391909.7 linkuse as main transcript	c.606G>A	p.Leu202=	synonymous_variant	4/4	2		P1
FKRP	ENST00000597339.5 linkuse as main transcript	n.247-5777G>A		intron_variant, non_coding_transcript_variant		5
FKRP	ENST00000600646.5 linkuse as main transcript	n.247+7391G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000618

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000141

AC:

AN:

191336

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

107376

show subpopulations

Gnomad AFR exome

AF:

0.00197

Gnomad AMR exome

AF:

0.000255

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000116

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000562

AC:

AN:

1424610

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

707842

show subpopulations

Gnomad4 AFR exome

AF:

0.00204

Gnomad4 AMR exome

AF:

0.000188

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:

9.07e-7

Gnomad4 OTH exome

AF:

0.000118

GnomAD4 genome

AF:

0.000657

AC:

100

AN:

152166

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00231

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000305

Hom.:

Bravo

AF:

0.000544

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2020	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

Autosomal recessive limb-girdle muscular dystrophy type 2I

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jul 13, 2021

- -

FKRP-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 15, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Walker-Warburg congenital muscular dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

2.9

DANN

Benign

0.63

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