rs3201779

Variant names:

• chr19-46755417-C-T
• rs3201779
• NM_024301.5:c.-34C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024301.5(FKRP):​c.-34C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,582,586 control chromosomes in the GnomAD database, including 43,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2881 hom., cov: 33)
  • Exomes 𝑓: 0.23 (40135 hom.)
• Consequence: FKRP NM_024301.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.15
• Publications: 5 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 19-46755417-C-T is Benign according to our data. Variant chr19-46755417-C-T is described in ClinVar as Benign. ClinVar VariationId is 96104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.244 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.-34C>T		5_prime_UTR	Exon 4 of 4	NP_077277.1
	FKRP	NM_001039885.3		c.-34C>T		5_prime_UTR	Exon 4 of 4	NP_001034974.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKRP	ENST00000318584.10	TSL:1 MANE Select	c.-34C>T		5_prime_UTR	Exon 4 of 4	ENSP00000326570.4
	FKRP	ENST00000391909.7	TSL:2	c.-34C>T		5_prime_UTR	Exon 4 of 4	ENSP00000375776.2
	FKRP	ENST00000908841.1		c.-34C>T		5_prime_UTR	Exon 3 of 3	ENSP00000578900.1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26349 AN: 152108 Hom.: 2878 Cov.: 33

Gnomad AFR AF: 0.0637

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.203

GnomAD2 exomes AF: 0.187 AC: 38453 AN: 206048 AF XY: 0.194

Gnomad AFR exome AF: 0.0581

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.261

Gnomad EAS exome AF: 0.000551

Gnomad FIN exome AF: 0.211

Gnomad NFE exome AF: 0.251

Gnomad OTH exome AF: 0.210

GnomAD4 exome AF: 0.229 AC: 327436 AN: 1430360 Hom.: 40135 Cov.: 31 AF XY: 0.229 AC XY: 162548 AN XY: 710476

African (AFR) AF: 0.0568 AC: 1865 AN: 32854

American (AMR) AF: 0.109 AC: 4620 AN: 42500

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 6597 AN: 25542

East Asian (EAS) AF: 0.000569 AC: 22 AN: 38674

South Asian (SAS) AF: 0.195 AC: 16285 AN: 83370

European-Finnish (FIN) AF: 0.214 AC: 8662 AN: 40570

Middle Eastern (MID) AF: 0.253 AC: 1361 AN: 5382

European-Non Finnish (NFE) AF: 0.250 AC: 275656 AN: 1102090

Other (OTH) AF: 0.208 AC: 12368 AN: 59378

GnomAD4 genome AF: 0.173 AC: 26351 AN: 152226 Hom.: 2881 Cov.: 33 AF XY: 0.171 AC XY: 12729 AN XY: 74438

African (AFR) AF: 0.0635 AC: 2640 AN: 41554

American (AMR) AF: 0.139 AC: 2129 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 928 AN: 3468

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5180

South Asian (SAS) AF: 0.177 AC: 854 AN: 4828

European-Finnish (FIN) AF: 0.210 AC: 2228 AN: 10602

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16820 AN: 67974

Other (OTH) AF: 0.200 AC: 423 AN: 2114

Alfa AF: 0.220 Hom.: 1684

Bravo AF: 0.163

Asia WGS AF: 0.0690 AC: 240 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2I (1)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 (1)
-	-	1	Muscular dystrophy-dystroglycanopathy type B5 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.0
DANN	Benign	0.73
PhyloP100		3.2
Mutation Taster		=300/0	polymorphism (auto)

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: rs3201779; hg19: chr19-47258674; COSMIC: COSV59358546; COSMIC: COSV59358546;