NM_024301.5:c.183C>T

Variant names:

• chr19-46755633-C-T
• rs759539583
• NM_024301.5:c.183C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_024301.5(FKRP):​c.183C>T​(p.Asn61Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,748 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FKRP NM_024301.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.290
• 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: 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_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP7: Synonymous conserved (PhyloP=0.29 with no splicing effect.

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.183C>T	p.Asn61Asn	synonymous	Exon 4 of 4	NP_077277.1	Q9H9S5
	FKRP	NM_001039885.3		c.183C>T	p.Asn61Asn	synonymous	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.183C>T	p.Asn61Asn	synonymous	Exon 4 of 4	ENSP00000326570.4	Q9H9S5
	FKRP	ENST00000594467.5	TSL:4	c.-247C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 3	ENSP00000471971.1	M0R1M1
	FKRP	ENST00000391909.7	TSL:2	c.183C>T	p.Asn61Asn	synonymous	Exon 4 of 4	ENSP00000375776.2	Q9H9S5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000437 AC: 1 AN: 228796 AF XY: 0.00000799

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: 0.00000956

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448748 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 720728

African (AFR) AF: 0.00 AC: 0 AN: 33306

American (AMR) AF: 0.00 AC: 0 AN: 44176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25948

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39380

South Asian (SAS) AF: 0.00 AC: 0 AN: 85174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109608

Other (OTH) AF: 0.00 AC: 0 AN: 60076

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.93
PhyloP100		0.29

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: rs759539583; hg19: chr19-47258890;