19-46755585-C-T

Variant names:

• chr19-46755585-C-T
• rs2287717
• NM_024301.5:c.135C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024301.5(FKRP):​c.135C>T​(p.Ala45Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,604,888 control chromosomes in the GnomAD database, including 16,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A45A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1588 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15045 hom.)
• Consequence: FKRP NM_024301.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -0.496
• Publications: 24 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-46755585-C-T is Benign according to our data. Variant chr19-46755585-C-T is described in ClinVar as Benign. ClinVar VariationId is 96105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.496 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

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.135C>T	p.Ala45Ala	synonymous	Exon 4 of 4	NP_077277.1	Q9H9S5
	FKRP	NM_001039885.3		c.135C>T	p.Ala45Ala	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.135C>T	p.Ala45Ala	synonymous	Exon 4 of 4	ENSP00000326570.4	Q9H9S5
	FKRP	ENST00000594467.5	TSL:4	c.-295C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 3	ENSP00000471971.1	M0R1M1
	FKRP	ENST00000391909.7	TSL:2	c.135C>T	p.Ala45Ala	synonymous	Exon 4 of 4	ENSP00000375776.2	Q9H9S5

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21466 AN: 152140 Hom.: 1583 Cov.: 33

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.142 AC: 32843 AN: 230836 AF XY: 0.143

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.130

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.143 AC: 208019 AN: 1452630 Hom.: 15045 Cov.: 34 AF XY: 0.144 AC XY: 103902 AN XY: 722134

African (AFR) AF: 0.151 AC: 5025 AN: 33288

American (AMR) AF: 0.144 AC: 6294 AN: 43702

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 3278 AN: 25920

East Asian (EAS) AF: 0.116 AC: 4551 AN: 39224

South Asian (SAS) AF: 0.174 AC: 14774 AN: 85092

European-Finnish (FIN) AF: 0.118 AC: 6040 AN: 51252

Middle Eastern (MID) AF: 0.107 AC: 617 AN: 5754

European-Non Finnish (NFE) AF: 0.144 AC: 159089 AN: 1108426

Other (OTH) AF: 0.139 AC: 8351 AN: 59972

GnomAD4 genome AF: 0.141 AC: 21484 AN: 152258 Hom.: 1588 Cov.: 33 AF XY: 0.138 AC XY: 10281 AN XY: 74444

African (AFR) AF: 0.151 AC: 6273 AN: 41552

American (AMR) AF: 0.128 AC: 1957 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 439 AN: 3472

East Asian (EAS) AF: 0.128 AC: 660 AN: 5176

South Asian (SAS) AF: 0.176 AC: 849 AN: 4828

European-Finnish (FIN) AF: 0.125 AC: 1331 AN: 10616

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9636 AN: 68000

Other (OTH) AF: 0.128 AC: 271 AN: 2114

Alfa AF: 0.138 Hom.: 609

Bravo AF: 0.143

Asia WGS AF: 0.158 AC: 549 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2I (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dystrophin deficiency (1)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 (1)
-	-	1	Muscular dystrophy-dystroglycanopathy type B5 (1)
-	-	1	Walker-Warburg congenital muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.3
DANN	Benign	0.72
PhyloP100		-0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2287717; hg19: chr19-47258842; COSMIC: COSV59359667; COSMIC: COSV59359667;