rs200990647

Variant names:

• chr19-46755970-A-C
• rs200990647
• NM_024301.5:c.520A>C

Your query was ambiguous. Multiple possible variants found:

• chr19-46755970-A-C
• chr19-46755970-A-G
• chr19-46755970-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_024301.5(FKRP):​c.520A>C​(p.Ser174Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,387,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S174C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy type 2I

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics
• muscular dystrophy-dystroglycanopathy type B5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• myopathy caused by variation in FKRP

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital muscular dystrophy with cerebellar involvement

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy with intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy without intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscle-eye-brain disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_024301.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 46 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.8498 (below the threshold of 3.09). Trascript score misZ: -2.4986 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive limb-girdle muscular dystrophy type 2I, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5, congenital muscular dystrophy with intellectual disability, muscular dystrophy-dystroglycanopathy, type A, muscle-eye-brain disease, congenital muscular dystrophy with cerebellar involvement, myopathy caused by variation in FKRP, muscular dystrophy-dystroglycanopathy type B5, congenital muscular dystrophy without intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.41246343).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5	c.520A>C	p.Ser174Arg	missense_variant	Exon 4 of 4	ENST00000318584.10	NP_077277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10	c.520A>C	p.Ser174Arg	missense_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1387376 Hom.: 0 Cov.: 32 AF XY: 0.00000146 AC XY: 1 AN XY: 685494

African (AFR) AF: 0.00 AC: 0 AN: 31432

American (AMR) AF: 0.00 AC: 0 AN: 35978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25072

East Asian (EAS) AF: 0.00 AC: 0 AN: 35980

South Asian (SAS) AF: 0.00 AC: 0 AN: 79400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081422

Other (OTH) AF: 0.0000173 AC: 1 AN: 57964

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.28	T;T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.79	.;T;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	0.34	N;N;.
PhyloP100		1.7
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.3	N;N;.
REVEL	Uncertain	0.52
Sift	Benign	0.062	T;T;.
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.0010	B;B;.
Vest4		0.21
MutPred		0.43		Gain of MoRF binding (P = 0.018);Gain of MoRF binding (P = 0.018);.;
MVP		0.83
MPC		0.99
ClinPred		0.13	T
GERP RS		3.5
Varity_R		0.39
gMVP		0.70
Mutation Taster		=48/52	disease causing

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

Other links and lift over

dbSNP: rs200990647; hg19: chr19-47259227;