rs77138370

Positions:

• chr19-46756272-C-G
• chr19-46756272-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024301.5(FKRP):​c.822C>G​(p.Ile274Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000592 in 1,508,888 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (5 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 1.13

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006845355).
• BP6: Variant 19-46756272-C-G is Benign according to our data. Variant chr19-46756272-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129058.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=3, Uncertain_significance=1}. Variant chr19-46756272-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00308 (467/151746) while in subpopulation AFR AF= 0.0103 (426/41508). AF 95% confidence interval is 0.00946. There are 3 homozygotes in gnomad4. There are 195 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKRP	NM_024301.5	c.822C>G	p.Ile274Met	missense_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.822C>G	p.Ile274Met	missense_variant	4/4	1	NM_024301.5	ENSP00000326570	P1
FKRP	ENST00000391909.7	c.822C>G	p.Ile274Met	missense_variant	4/4	2		ENSP00000375776	P1
FKRP	ENST00000597339.5	n.247-5561C>G		intron_variant, non_coding_transcript_variant		5
FKRP	ENST00000600646.5	n.247+7607C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00307 AC: 466 AN: 151638 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000868

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.000687 AC: 79 AN: 114982 Hom.: 0 AF XY: 0.000493 AC XY: 31 AN XY: 62924

Gnomad AFR exome AF: 0.00962

Gnomad AMR exome AF: 0.000555

Gnomad ASJ exome AF: 0.000943

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000533

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000466

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000315 AC: 427 AN: 1357142 Hom.: 5 Cov.: 32 AF XY: 0.000250 AC XY: 167 AN XY: 667508

Gnomad4 AFR exome AF: 0.0109

Gnomad4 AMR exome AF: 0.000586

Gnomad4 ASJ exome AF: 0.000904

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000265

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000752

Gnomad4 OTH exome AF: 0.000709

GnomAD4 genome AF: 0.00308 AC: 467 AN: 151746 Hom.: 3 Cov.: 33 AF XY: 0.00263 AC XY: 195 AN XY: 74142

Gnomad4 AFR AF: 0.0103

Gnomad4 AMR AF: 0.00184

Gnomad4 ASJ AF: 0.000868

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000443

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000685 Hom.: 0

Bravo AF: 0.00346

ESP6500AA AF: 0.00149 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000418 AC: 40

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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)	Dec 27, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2021	This variant is associated with the following publications: (PMID: 27142102) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jun 05, 2020

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2019

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

Likely 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
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.59
DEOGEN2	Uncertain	0.52	D;D
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.45	.;T
MetaRNN	Benign	0.0068	T;T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	-0.29	N;N
MutationTaster	Benign	0.89	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.043	D;D
Sift4G	Benign	0.061	T;T
Polyphen		0.0080	B;B
Vest4		0.28
MVP		0.83
MPC		0.65
ClinPred		0.0077	T
GERP RS		1.8
Varity_R		0.55
gMVP		0.86

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: rs77138370; hg19: chr19-47259529;