NM_024301.5:c.249C>T

Variant names:

• chr19-46755699-C-T
• rs149030303
• NM_024301.5:c.249C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_024301.5(FKRP):​c.249C>T​(p.Ala83Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,582,434 control chromosomes in the GnomAD database, including 174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (16 hom., cov: 33)
  • Exomes 𝑓: 0.013 (158 hom.)
• Consequence: FKRP NM_024301.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -2.99
• Publications: 6 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 19-46755699-C-T is Benign according to our data. Variant chr19-46755699-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00925 (1409/152330) while in subpopulation SAS AF = 0.0186 (90/4828). AF 95% confidence interval is 0.0155. There are 16 homozygotes in GnomAd4. There are 697 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

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.249C>T	p.Ala83Ala	synonymous	Exon 4 of 4	NP_077277.1	Q9H9S5
	FKRP	NM_001039885.3		c.249C>T	p.Ala83Ala	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.249C>T	p.Ala83Ala	synonymous	Exon 4 of 4	ENSP00000326570.4	Q9H9S5
	FKRP	ENST00000594467.5	TSL:4	c.-181C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 3	ENSP00000471971.1	M0R1M1
	FKRP	ENST00000391909.7	TSL:2	c.249C>T	p.Ala83Ala	synonymous	Exon 4 of 4	ENSP00000375776.2	Q9H9S5

Frequencies

GnomAD3 genomes AF: 0.00929 AC: 1414 AN: 152212 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0192

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.0107 AC: 2147 AN: 200206 AF XY: 0.0118

Gnomad AFR exome AF: 0.00247

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0149

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0133 AC: 19023 AN: 1430104 Hom.: 158 Cov.: 33 AF XY: 0.0136 AC XY: 9678 AN XY: 710616

African (AFR) AF: 0.00222 AC: 73 AN: 32878

American (AMR) AF: 0.00230 AC: 100 AN: 43570

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 298 AN: 25678

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38344

South Asian (SAS) AF: 0.0179 AC: 1500 AN: 83892

European-Finnish (FIN) AF: 0.0136 AC: 513 AN: 37806

Middle Eastern (MID) AF: 0.0195 AC: 112 AN: 5734

European-Non Finnish (NFE) AF: 0.0143 AC: 15780 AN: 1102844

Other (OTH) AF: 0.0109 AC: 646 AN: 59358

GnomAD4 genome AF: 0.00925 AC: 1409 AN: 152330 Hom.: 16 Cov.: 33 AF XY: 0.00936 AC XY: 697 AN XY: 74494

African (AFR) AF: 0.00252 AC: 105 AN: 41588

American (AMR) AF: 0.00405 AC: 62 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0186 AC: 90 AN: 4828

European-Finnish (FIN) AF: 0.0156 AC: 166 AN: 10628

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0135 AC: 921 AN: 68008

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.0118 Hom.: 5

Bravo AF: 0.00767

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	not provided (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2I (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	Walker-Warburg congenital muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	1.7
DANN	Benign	0.92
PhyloP100		-3.0
Mutation Taster		=100/0	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: rs149030303; hg19: chr19-47258956; COSMIC: COSV106059521; COSMIC: COSV106059521;