19-46755585-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024301.5(FKRP):c.135C>T(p.Ala45=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,604,888 control chromosomes in the GnomAD database, including 16,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A45A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1588 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15045 hom.)
• Consequence: FKRP NM_024301.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.496

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-46755585-C-T is Benign according to our data. Variant chr19-46755585-C-T is described in ClinVar as [Benign]. Clinvar id is 96105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755585-C-T is described in Lovd as [Benign]. Variant chr19-46755585-C-T is described in Lovd as [Pathogenic]. Variant chr19-46755585-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.496 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKRP	NM_024301.5	c.135C>T	p.Ala45=	synonymous_variant	4/4	ENST00000318584.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKRP	ENST00000318584.10	c.135C>T	p.Ala45=	synonymous_variant	4/4	1	NM_024301.5	P1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21466 AN: 152140 Hom.: 1583 Cov.: 33

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.128

GnomAD3 exomes AF: 0.142 AC: 32843 AN: 230836 Hom.: 2335 AF XY: 0.143 AC XY: 18006 AN XY: 125774

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.130

Gnomad SAS exome AF: 0.172

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.143 AC: 208019 AN: 1452630 Hom.: 15045 Cov.: 34 AF XY: 0.144 AC XY: 103902 AN XY: 722134

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.144

Gnomad4 ASJ exome AF: 0.126

Gnomad4 EAS exome AF: 0.116

Gnomad4 SAS exome AF: 0.174

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.144

Gnomad4 OTH exome AF: 0.139

GnomAD4 genome AF: 0.141 AC: 21484 AN: 152258 Hom.: 1588 Cov.: 33 AF XY: 0.138 AC XY: 10281 AN XY: 74444

Gnomad4 AFR AF: 0.151

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.126

Gnomad4 EAS AF: 0.128

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.128

Alfa AF: 0.138 Hom.: 609

Bravo AF: 0.143

Asia WGS AF: 0.158 AC: 549 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Ala45Ala in exon 4 of FKRP: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 14.2% (625/4398) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs2287717). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 11, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Autosomal recessive limb-girdle muscular dystrophy type 2I Benign:2

Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

Muscular dystrophy-dystroglycanopathy type B5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 28, 2017

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Dystrophin deficiency Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2018

This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	2.3
Dann	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs2287717; hg19: chr19-47258842; COSMIC: COSV59359667; COSMIC: COSV59359667;