rs1555738483

Positions:

• chr19-46755952-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_024301.5(FKRP):​c.502T>C​(p.Cys168Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000145 in 1,383,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 4.30

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835
• PP5: Variant 19-46755952-T-C is Pathogenic according to our data. Variant chr19-46755952-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 557519.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}. Variant chr19-46755952-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKRP	NM_024301.5	c.502T>C	p.Cys168Arg	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.502T>C	p.Cys168Arg	missense_variant	4/4	1	NM_024301.5	ENSP00000326570.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1383754 Hom.: 0 Cov.: 32 AF XY: 0.00000146 AC XY: 1 AN XY: 683176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 09, 2023

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 28, 2018

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 26, 2024

Variant summary: FKRP c.502T>C (p.Cys168Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.502T>C has been reported in the literature in one individual affected with congenital muscular dystrophy type 1C, Autosomal Recessive (Fu_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27439679, 32864802). ClinVar contains an entry for this variant (Variation ID: 557519). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;D;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.060
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.57	.;T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	1.8	L;L;.
PrimateAI	Pathogenic	0.98	D
PROVEAN	Pathogenic	-7.8	D;D;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.93
MutPred		0.63		Gain of MoRF binding (P = 0.0037);Gain of MoRF binding (P = 0.0037);.;
MVP		0.88
MPC		2.2
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.97
gMVP		0.98

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: rs1555738483; hg19: chr19-47259209;