NM_024301.5:c.706C>A

Variant names:

• chr19-46756156-C-A
• rs754347622
• NM_024301.5:c.706C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_024301.5(FKRP):​c.706C>A​(p.Leu236Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000761 in 1,314,112 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. L236P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.68
• 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 2 ACMG points.

• 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=0.40637952).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5	c.706C>A	p.Leu236Met	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.706C>A	p.Leu236Met	missense_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.61e-7 AC: 1 AN: 1314112 Hom.: 0 Cov.: 32 AF XY: 0.00000155 AC XY: 1 AN XY: 647098

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25874

American (AMR) AF: 0.00 AC: 0 AN: 23818

Ashkenazi Jewish (ASJ) AF: 0.0000453 AC: 1 AN: 22068

East Asian (EAS) AF: 0.00 AC: 0 AN: 29508

South Asian (SAS) AF: 0.00 AC: 0 AN: 70982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5430

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1048710

Other (OTH) AF: 0.00 AC: 0 AN: 54462

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T;T
Eigen	Benign	0.046
Eigen_PC	Benign	0.050
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.37	.;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L;L
PhyloP100		1.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.84	N;N
REVEL	Uncertain	0.58
Sift	Benign	0.10	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.65	P;P
Vest4		0.32
MutPred		0.38		Gain of catalytic residue at L236 (P = 0.0013);Gain of catalytic residue at L236 (P = 0.0013);
MVP		0.80
MPC		0.68
ClinPred		0.70	D
GERP RS		4.1
Varity_R		0.41
gMVP		0.71
Mutation Taster		=54/46	polymorphism

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: rs754347622; hg19: chr19-47259413;