19-46756276-C-A

Variant names:

• chr19-46756276-C-A
• rs28937900
• NM_024301.5:c.826C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 9P and 3B. PP2 PP5_Very_Strong BP4 BS1_Supporting BS2_Supporting

The NM_024301.5(FKRP):​c.826C>A​(p.Leu276Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,516,960 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L276L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (2 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:54
• Conservation: PhyloP100: 1.80
• Publications: 150 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: Likely_pathogenic. The variant received 6 ACMG points.

• 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.
• PP5: Variant 19-46756276-C-A is Pathogenic according to our data. Variant chr19-46756276-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009812146). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00207 (2826/1365112) while in subpopulation NFE AF = 0.00251 (2684/1068114). AF 95% confidence interval is 0.00243. There are 2 homozygotes in GnomAdExome4. There are 1356 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.826C>A	p.Leu276Ile	missense	Exon 4 of 4	NP_077277.1	Q9H9S5
	FKRP	NM_001039885.3		c.826C>A	p.Leu276Ile	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.826C>A	p.Leu276Ile	missense	Exon 4 of 4	ENSP00000326570.4	Q9H9S5
	FKRP	ENST00000391909.7	TSL:2	c.826C>A	p.Leu276Ile	missense	Exon 4 of 4	ENSP00000375776.2	Q9H9S5
	FKRP	ENST00000908841.1		c.826C>A	p.Leu276Ile	missense	Exon 3 of 3	ENSP00000578900.1

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 151740 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000476

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00103 AC: 125 AN: 121630 AF XY: 0.00108

Gnomad AFR exome AF: 0.000158

Gnomad AMR exome AF: 0.000266

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00162

GnomAD4 exome AF: 0.00207 AC: 2826 AN: 1365112 Hom.: 2 Cov.: 32 AF XY: 0.00202 AC XY: 1356 AN XY: 672092

African (AFR) AF: 0.000387 AC: 12 AN: 31022

American (AMR) AF: 0.000328 AC: 11 AN: 33540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23658

East Asian (EAS) AF: 0.00 AC: 0 AN: 35340

South Asian (SAS) AF: 0.00 AC: 0 AN: 76556

European-Finnish (FIN) AF: 0.00147 AC: 52 AN: 35342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4802

European-Non Finnish (NFE) AF: 0.00251 AC: 2684 AN: 1068114

Other (OTH) AF: 0.00118 AC: 67 AN: 56738

GnomAD4 genome AF: 0.00109 AC: 166 AN: 151848 Hom.: 0 Cov.: 32 AF XY: 0.000997 AC XY: 74 AN XY: 74214

African (AFR) AF: 0.000434 AC: 18 AN: 41514

American (AMR) AF: 0.000393 AC: 6 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000476 AC: 5 AN: 10506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00201 AC: 136 AN: 67792

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.00102

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000662 AC: 4

ExAC AF: 0.000925 AC: 92

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
17	-	-	not provided (17)
12	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2I (12)
4	-	-	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 (4)
3	-	-	Muscular dystrophy-dystroglycanopathy type B5 (3)
2	-	-	FKRP-related disorder (2)
2	-	-	Limb-girdle muscular dystrophy (2)
2	-	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 (2)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy (1)
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	-	-	FKRP-related muscular dystrophy-dystroglycanopathy (1)
1	-	-	Headache;C0030554:Paresthesia;C0151786:Muscle weakness;C0239067:Difficulty climbing stairs;C0240953:Scapular winging;C0241237:Difficulty standing;C0311394:Difficulty walking;C1836150:Gait imbalance (1)
1	-	-	Hereditary skeletal muscle disorder (1)
1	-	-	Muscular dystrophy-dystroglycanopathy (1)
1	-	-	Myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.049
Eigen_PC	Benign	0.058
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0098	T
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	1.4	L
PhyloP100		1.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.85	N
REVEL	Pathogenic	0.70
Sift	Benign	0.065	T
Sift4G	Benign	0.066	T
Polyphen		0.85	P
Vest4		0.56
MVP		0.87
MPC		1.2
ClinPred		0.025	T
GERP RS		4.2
Varity_R		0.47
gMVP		0.62
Mutation Taster		=23/77	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: rs28937900; hg19: chr19-47259533; COSMIC: COSV100586706; COSMIC: COSV100586706;