rs104894681

Variant names:

• chr19-46756793-C-T
• rs104894681
• NM_024301.5:c.1343C>T

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_024301.5(FKRP):​c.1343C>T​(p.Pro448Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,601,034 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002688773: "Additionally, both in vitro and in vivo assays showed this alteration impacts protein function, including a homozygous knock-in mouse that showed this alteration almost completely lacks functional glycosylation of alpha-dystroglycan in muscles and brain (Esapa CT et al. Hum Mol Genet, 2002 Dec" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P448P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.74
• Publications: 65 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: Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• 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: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002688773: "Additionally, both in vitro and in vivo assays showed this alteration impacts protein function, including a homozygous knock-in mouse that showed this alteration almost completely lacks functional glycosylation of alpha-dystroglycan in muscles and brain (Esapa CT et al. Hum Mol Genet, 2002 Dec;11:3319-31; Esapa CT et al. Hum Mol Genet, 2005 Jan;14:295-305; Keramaris-Vrantsis E et al. Muscle Nerve, 2007 Oct;36:455-65; Lu PJ et al. Biochim Biophys Acta, 2010 Feb;1802:253-8; Chan YM et al. Hum Mol Genet, 2010 Oct;19:3995-4006; Maricelli JW et al. PLoS One, 2016 Sep;11:e0161984; Blaeser A et al. PLoS One, 2016 Oct;11:e0164187)."; SCV004276080: Experimental studies have shown that this missense change affects FKRP function (PMID: 12471058, 15574464, 19900540, 20675713, 27711214, 29858056, 30417025).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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 muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5, muscle-eye-brain disease, congenital muscular dystrophy with cerebellar involvement, muscular dystrophy-dystroglycanopathy, type A, autosomal recessive limb-girdle muscular dystrophy type 2I, muscular dystrophy-dystroglycanopathy type B5, congenital muscular dystrophy without intellectual disability, myopathy caused by variation in FKRP, congenital muscular dystrophy with intellectual disability.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 19-46756793-C-T is Pathogenic according to our data. Variant chr19-46756793-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024301.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKRP	NM_024301.5	MANE Select	c.1343C>T	p.Pro448Leu	missense	Exon 4 of 4	NP_077277.1	Q9H9S5
	FKRP	NM_001039885.3		c.1343C>T	p.Pro448Leu	missense	Exon 4 of 4	NP_001034974.1	Q9H9S5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKRP	ENST00000318584.10	TSL:1 MANE Select	c.1343C>T	p.Pro448Leu	missense	Exon 4 of 4	ENSP00000326570.4	Q9H9S5
	FKRP	ENST00000391909.7	TSL:2	c.1343C>T	p.Pro448Leu	missense	Exon 4 of 4	ENSP00000375776.2	Q9H9S5
	FKRP	ENST00000908841.1		c.1343C>T	p.Pro448Leu	missense	Exon 3 of 3	ENSP00000578900.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000897 AC: 2 AN: 222986 AF XY: 0.00000825

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448714 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719810

African (AFR) AF: 0.0000301 AC: 1 AN: 33190

American (AMR) AF: 0.00 AC: 0 AN: 42684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25790

East Asian (EAS) AF: 0.00 AC: 0 AN: 39060

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106368

Other (OTH) AF: 0.00 AC: 0 AN: 59952

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000433 Hom.: 0

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	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 (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 (1)
1	-	-	Muscular dystrophy-dystroglycanopathy (congenital without impaired intellectual development), type B, 5 (1)
1	-	-	Walker-Warburg congenital muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-8.2	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.81		Gain of helix (P = 0.0117)
MVP		0.98
MPC		1.7
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.75
gMVP		0.86
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs104894681; hg19: chr19-47260050;