rs75079578

Positions:

• chr19-46756035-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024301.5(FKRP):​c.585C>T​(p.Asp195Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,579,756 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (19 hom., cov: 33)
  • Exomes 𝑓: 0.00099 (20 hom.)
• Consequence: FKRP NM_024301.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -3.01

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 19-46756035-C-T is Benign according to our data. Variant chr19-46756035-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 96112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46756035-C-T is described in Lovd as [Pathogenic]. Variant chr19-46756035-C-T is described in Lovd as [Benign]. Variant chr19-46756035-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.01 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00997 (1516/152028) while in subpopulation AFR AF= 0.0325 (1350/41492). AF 95% confidence interval is 0.0311. There are 19 homozygotes in gnomad4. There are 686 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKRP	NM_024301.5	c.585C>T	p.Asp195Asp	synonymous_variant	4/4	ENST00000318584.10	NP_077277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10	c.585C>T	p.Asp195Asp	synonymous_variant	4/4	1	NM_024301.5	ENSP00000326570.4
FKRP	ENST00000391909.7	c.585C>T	p.Asp195Asp	synonymous_variant	4/4	2		ENSP00000375776.2
FKRP	ENST00000597339.5	n.247-5798C>T		intron_variant		5
FKRP	ENST00000600646.5	n.247+7370C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00995 AC: 1511 AN: 151918 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00825

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00204 AC: 398 AN: 194854 Hom.: 5 AF XY: 0.00158 AC XY: 172 AN XY: 108910

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.000906

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000369

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000126

Gnomad OTH exome AF: 0.00120

GnomAD4 exome AF: 0.000987 AC: 1409 AN: 1427728 Hom.: 20 Cov.: 32 AF XY: 0.000816 AC XY: 579 AN XY: 709610

Gnomad4 AFR exome AF: 0.0332

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.000902

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.0000360

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000716

Gnomad4 OTH exome AF: 0.00239

GnomAD4 genome AF: 0.00997 AC: 1516 AN: 152028 Hom.: 19 Cov.: 33 AF XY: 0.00923 AC XY: 686 AN XY: 74336

Gnomad4 AFR AF: 0.0325

Gnomad4 AMR AF: 0.00818

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00334 Hom.: 1

Bravo AF: 0.0115

Asia WGS AF: 0.00290 AC: 10 AN: 3458

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2015	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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 21, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 11, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 21, 2021

- -

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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 24, 2017

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 24, 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.8
DANN	Benign	0.74

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

Other links and lift over

dbSNP: rs75079578; hg19: chr19-47259292;