rs201454433

chr19-46756017-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_024301.5(FKRP):c.567C>T(p.Pro189=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000303 in 1,572,228 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P189P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: FKRP NM_024301.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.801

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-46756017-C-T is Benign according to our data. Variant chr19-46756017-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261691.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}. Variant chr19-46756017-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.801 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00134 (204/151968) while in subpopulation AFR AF= 0.00458 (190/41492). AF 95% confidence interval is 0.00405. There are 0 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKRP	NM_024301.5	c.567C>T	p.Pro189=	synonymous_variant	4/4	ENST00000318584.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKRP	ENST00000318584.10	c.567C>T	p.Pro189=	synonymous_variant	4/4	1	NM_024301.5	P1

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 203 AN: 151858 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00457

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000334 AC: 61 AN: 182622 Hom.: 0 AF XY: 0.000275 AC XY: 28 AN XY: 101966

Gnomad AFR exome AF: 0.00460

Gnomad AMR exome AF: 0.000166

Gnomad ASJ exome AF: 0.000463

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000385

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000497

Gnomad OTH exome AF: 0.000830

GnomAD4 exome AF: 0.000192 AC: 272 AN: 1420260 Hom.: 2 Cov.: 32 AF XY: 0.000176 AC XY: 124 AN XY: 705172

Gnomad4 AFR exome AF: 0.00529

Gnomad4 AMR exome AF: 0.000170

Gnomad4 ASJ exome AF: 0.000354

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000336

Gnomad4 OTH exome AF: 0.000694

GnomAD4 genome AF: 0.00134 AC: 204 AN: 151968 Hom.: 0 Cov.: 33 AF XY: 0.00131 AC XY: 97 AN XY: 74306

Gnomad4 AFR AF: 0.00458

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000948 Hom.: 0

Bravo AF: 0.00144

Asia WGS AF: 0.000581 AC: 2 AN: 3458

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	FKRP: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2020	This variant is associated with the following publications: (PMID: 14647208) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2016

- -

Autosomal recessive limb-girdle muscular dystrophy type 2I Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 24, 2019

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 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

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	-0.82
Cadd	Benign	4.4
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs201454433; hg19: chr19-47259274;